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Chest. May 2009; 135(5): 1223–1232.
PMCID: PMC2818415

Efficacy and Safety of Inhaled Aztreonam Lysine for Airway Pseudomonas in Cystic Fibrosis

Abstract

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; ≥ 6 years of age) with FEV1 ≥ 25% and ≤ 75% predicted values, and no recent use of antipseudomonal antibiotics or azithromycin were treated with 75 mg of AZLI (three times daily for 28 days) or placebo (1:1 randomization), then were monitored for 14 days after study drug completion. The primary efficacy end point was change in patient-reported respiratory symptoms (CF-Questionnaire-Revised [CFQ-R] Respiratory Scale). Secondary end points included changes in pulmonary function (FEV1), sputum PA density, and nonrespiratory CFQ-R scales. Adverse events and minimum inhibitory concentrations of aztreonam for PA were monitored.

Results:

After 28 days of treatment, AZLI improved the mean CFQ-R respiratory score (9.7 points; p < 0.001), FEV1 (10.3% predicted; p < 0.001), and sputum PA density (− 1.453 log10 cfu/g; p < 0.001), compared with placebo. Significant improvements in Eating, Emotional Functioning, Health Perceptions, Physical Functioning, Role Limitation/School Performance, and Vitality CFQ-R scales were observed. Adverse events were consistent with symptoms of CF lung disease and were comparable for AZLI and placebo except the incidence of “productive cough” was reduced by half in AZLI-treated patients. PA aztreonam susceptibility at baseline and end of therapy were similar.

Conclusions:

In patients with CF, PA airway infection, moderate-to-severe lung disease, and no recent use of antipseudomonal antibiotics or azithromycin, 28-day treatment with AZLI significantly improved respiratory symptoms and pulmonary function, and was well tolerated.

Trial registration:

Clinicaltrials.gov Identifier: NCT00112359

Keywords: aztreonam, cystic fibrosis, inhaled antibiotics, patient-reported outcomes, Pseudomonas, respiratory symptoms

Clinical management of cystic fibrosis (CF) has improved during the past 15 years. Increased standardization of care and a focus on maintenance therapies, including nutrition, combined with the introduction of dornase alfa in 1993, tobramycin inhalation solution (TIS) in 1998, and the widespread long-term use of azithromycin (a macrolide antibiotic) have been associated with an approximate 8-year increase in median predicted survival age (increase from 1990 to 2005 to 36.5 years of age) and a 10% increase in median FEV1 percent predicted (from 1990 to 2005).15 However, a sizable proportion of patients with CF do not receive long-term TIS or macrolide therapy. In 2005, among US patients in a national registry who were ≥ 6 years of age with CF and Pseudomonas aeruginosa (PA) airway infection, 42% of patients were not receiving long-term TIS therapy, and 46% of patients who were eligible for long-term macrolide therapy were not receiving it.1 Lack of compliance likely further reduces the number of patients receiving therapy; in one recent study, dosing compliance ranged from 51% (older patients) to 73% (younger patients).6 The reasons underlying the lack of treatment may include a lack of clinical response or drug availability, patient or physician preference, or drug intolerance. Additional antimicrobial treatment options are needed for treating chronic PA airway infection and may improve the health of these less intensively treated patients.

Aztreonam lysine for inhalation (AZLI) is an aerosolized formulation of the monobactam antibiotic, aztreonam, and lysine.7 The IV aztreonam formulation contains arginine, which can cause airway inflammation after long-term inhalation in patients with CF.8,9 In a previous study,10 AZLI increased the time to the need for additional inhaled or IV antipseudomonal antibiotics to treat symptoms indicative of pulmonary exacerbation; enrolled patients were generally compliant with current guidelines for CF care. In contrast, the study we report herein included patients receiving less maintenance therapy than currently recommended.11 Patients had not recently received therapy with antipseudomonal antibiotics, azithromycin, or aerosolized hypertonic saline solution. The study hypothesis was that treatment with AZLI, when compared with placebo, would produce a clinically significant improvement in patient-reported respiratory symptoms. The primary efficacy end point was the change in clinical symptoms, measured with the Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Scale (CFQ-R-respiratory). The Cystic Fibrosis Questionnaire-Revised (CFQ-R) is a validated, health-related, quality-of-life measure meeting the most recent US Food and Drug Administration draft guidelines on patient-reported outcomes (PROs).1215

Materials and Methods

Study Design

This randomized, double-blind, placebo-controlled, study was conducted at 53 CF centers (in Australia, Canada, New Zealand, and the United States; June 2005 to April 2007). At baseline (day 0), patients were stratified by CF disease severity (moderate disease, FEV1 > 50% to ≤ 75% predicted; severe disease, FEV1 ≥ 25% to ≤ 50% predicted; measured at screening) and randomly assigned to 28 days of treatment with 75 mg of AZLI or placebo (randomized 1:1; administered three times daily). Patients were monitored at midtreatment (day 14), at treatment end (day 28), and at study end (day 42) [Fig 1]. Randomization was accomplished through a Web-based system using a computer-generated randomization schedule. This centralized randomization was stratified by baseline disease severity (FEV1 ≤ 50% or > 50% predicted) and employed a block size of 4.

Figure 1
Study design and patient disposition.

A physical examination was performed at screening. Spirometry, using American Thoracic Society standards16 was performed at every visit, before and 30 min after any treatment. FEV1 percent predicted values were calculated using the equation of Knudson et al.17

AZLI (75 mg of aztreonam, 52.5 mg of lysine monohydrate) or placebo (5 mg of lactose), diluted in 1 mL of a 0.17% NaCl solution, were administered with a nebulizer (eFlow Electronic Nebulizer; PARI Innovative Manufacturers; Midlothian, VA).18 Patients self-administered a short-acting β2-agonist 15 min before spirometry measurements were made and study medication was administered at clinic visits, and self-administered a β2-agonist before administering the study medication at home (within 2 h before dosing for short-acting agents, or 30 min to 8 h before dosing for long-acting agents). Patients continued any prescribed bronchodilator use, excluding a 4-h period before study visits. Study medication was dispensed at baseline; used/unused vials were subsequently collected to assess treatment compliance.

This study was conducted in compliance with the Declaration of Helsinki, the International Conference on Harmonisation guideline for Good Clinical Practices, and the applicable regulations for each participating country. Institutional review boards (in the United States) and ethics committees (in Canada, Australia, and New Zealand) approved the study for each site, and all patients or their guardians provided written informed consent or assent prior to undergoing any study procedures.

Study Population

Patients enrolled into the study were ≥ 6 years of age with a documented CF diagnosis, and had moderate-to-severe lung disease (FEV1 ≥ 25% to ≤ 75% predicted), arterial oxygen saturation ≥ 90% on room air (at screening), the ability to perform reproducible pulmonary function tests, and PA airway infection (documented at screening or twice within previous year, including once within the previous 3 months) without regard to PA susceptibility to aztreonam. Exclusion criteria included recent (ie, day −28 to screening) administration of inhaled, IV, or oral antipseudomonal antibiotics, azithromycin, or aerosolized hypertonic saline solution; current oral corticosteroid use equivalent to > 10 mg of prednisone daily; airway cultures yielding Burkholderia cepacia complex (previous 2 years); daily continuous oxygen supplementation or > 2 L/min at night; monobactam antibiotic hypersensitivity; intolerance to inhaled short-acting β2-agonists; recent changes in antimicrobial, bronchodilator, antiinflammatory, or corticosteroid medications, or physiotherapy technique/schedule; lung transplantation; new findings on chest radiograph at screening or in the previous 90 days; aspartate aminotransferase or alanine aminotransferase levels more than five times the upper limit of normal (at screening), or serum creatinine levels more than two times the upper limit of normal (at screening); pregnancy; lactation; or, in the opinion of the investigator, medical or psychiatric illness interfering with study participation. Patients were not permitted to use other antipseudomonal antibiotics or azithromycin during the study or during the 14-day follow-up period, unless required for the treatment of worsening symptoms.

Efficacy Measures

The CFQ-R was administered at baseline and at every visit thereafter. Unless noted, responses to adult, teen, and child versions were combined for presentation.14 The primary efficacy end point was change in symptoms, assessed with CFQ-R-Respiratory scores (range, 0 to 100 points; increasing scores indicated improvement). The minimal clinically important difference (MCID) corresponds to the smallest change in symptoms that a patient can detect and is used to interpret responses to PROs.19,20 An MCID score of 5 was previously determined for the CFQ-R-Respiratory Scale in stable patients.21 Thus, 5-point changes in scores reflected improved or worsened respiratory symptoms detected by patients.

Secondary end points included changes in pulmonary function, hospitalizations, nonrespiratory CFQ-R scales, sputum PA density (in colony-forming units per gram sputum, log10 transformed), the minimum inhibitory concentration (MIC) of aztreonam for PA, the number of isolates and proportion of patients with an aztreonam MIC > 8 μg/mL for PA (ie, the parenteral breakpoint), and the prevalence of other pathogens.22

Safety Measures

Adverse events and changes in clinical laboratory values, vital signs, and airway reactivity were monitored. Worsening CF symptoms were treated as adverse events. Patients requiring therapy with nonstudy antipseudomonal antibiotics discontinued their participation in the study.

Statistical Analysis

Efficacy and safety analyses included all randomly assigned patients receiving one or more doses of AZLI/placebo. FEV1 and CFQ-R analyses used the last-observation-carried-forward convention. Changes in FEV1 (in liters) and changes in FEV1 percent predicted were analyzed using relative values; increases and decreases were calculated as percentages of baseline FEV1 or FEV1 percent predicted values.

A sample size of 140 was estimated to provide 77% power to detect an 8-point difference for change in CFQ-R-Respiratory scores (assuming an SD of 20) and > 90% power to detect a 9% difference in FEV1 (assuming an SD of 12), with two-sided α = 0.05.

Continuous variables were analyzed using analysis of covariance models with treatment as the fixed effect; disease severity (moderate/severe) and baseline values (except analysis of log10 PA colony-forming units in sputum) were covariates. At day 28, patients were categorized as improved (a ≥ 5-point increase from baseline CFQ-R-Respiratory scores), worse (a ≥ 5-point decrease from baseline), or stable/no change (a < 5-point change). These categories were analyzed with the Cochran-Mantel-Haenszel mean score statistic; disease severity and baseline score were stratification variables.

Hospitalizations were analyzed using the Wilcoxon rank sum test (days) and Fisher exact test (proportion of patients). The aztreonam MIC inhibiting the growth of 50% of PA isolates (MIC50) or the aztreonam MIC inhibiting the growth of 90% of PA isolates (MIC90) and the presence of other pathogenic bacteria were summarized (Covance Central Laboratory Services; Indianapolis, IN) as were plasma and sputum aztreonam concentrations (Alta Analytical Laboratory; El Dorado Hills, CA).22 A statistical software package (SAS, versions 8.02 and 9.1; SAS Institute Inc; Cary, NC) was used for analyses.

Results

Of the 253 patients screened, 164 began treatment with AZLI or placebo, 138 completed 28 days of treatment, and 124 completed the study (Fig 1). The compliance rate for dosing (≥ 80% of doses) was 92%. The most common reason for discontinuation of participation in the study during the 28-day treatment period was an adverse event (ALZI group, 6 patients [7.5%]; placebo group, 13 patients [15.5%]) [Fig 1]; most of these patients (16 of 19 patients) required treatment with nonstudy antipseudomonal antibiotics and had symptoms indicative of pulmonary exacerbation. The remaining three patients (all randomized to receive placebo) discontinued study participation due to hospitalizations for bowel obstruction (n = 1), for umbilical hernia requiring surgery (n = 1), or for Staphylococcus aureus bacteremia, volume depletion, vancomycin-resistant Enterococcus and Pseudomonas septicemia, and deep vein thrombosis of the upper left arm (n = 1).

Patient Characteristics

Demographic characteristics were well balanced between treatment groups (Table 1). The mean age was 29.6 years. Most patients (77.4%) were ≥ 18 years of age. At baseline, mean the FEV1 was 54.6% predicted. The concomitant medications used by ≥ 40% patients at baseline included pancreatic enzymes (87%), vitamins (87%), salbutamol (79%), dornase alfa (65%), and fluticasone propionate with salmeterol xinafoate (40%).

Table 1
Patient Demographics and Baseline Characteristics*

Efficacy

The adjusted mean CFQ-R-Respiratory scores increased for AZLI-treated patients and decreased for placebo-treated patients (day 28 treatment difference, 9.7 points; 95% confidence interval [CI], 4.3 to 15.1; p < 0.001) [Fig 2, left, Table 2]. Two weeks after treatment, scores had declined but remained above baseline values for AZLI-treated patients, and had continued to decline for placebo-treated patients (day 42 treatment difference, 6.3 points; 95% CI, 1.2 to 11.4; p = 0.015) [Fig 2, left].

Figure 2
Left: adjusted mean CFQ-R-respiratory scores, FEV1, and sputum PA density; change from baseline to study end (days 0 to 42). Child, teen, and adult responses were combined for CFQ-R-Respiratory scores. Right: change from baseline to end of treatment for ...
Table 2
CFQ-R Scales: Change in Score From Baseline to End of Treatment (Days 0 to 28)

CFQ-R-Respiratory scores increased for AZLI-treated patients with differing disease severities and ages (Fig 2, right). Treatment effects were comparable in magnitude for patients with moderate or severe lung disease and were larger for younger patients (ie, those < 18 years of age).

CFQ-R-Respiratory scores improved for more AZLI-treated patients than placebo-treated patients (day 28; ≥ 5-point increase: AZLI group, 45 patients [56%]; placebo group, 31 patients [37%]). Scores also worsened for fewer AZLI-treated patients (≥ 5-point decrease: AZLI group, 20 patients [25%]; placebo group, 37 patients [45%]; p = 0.006 for overall comparison).

The adjusted mean FEV1 increased for AZLI-treated patients and decreased for placebo-treated patients (day 28 treatment difference, 10.3%; 95% CI, 6.3 to 14.3; p < 0.001) [Fig 2, left]. Two weeks after treatment, the mean FEV1 had declined but remained above baseline for AZLI-treated patients, and had continued to decline for placebo-treated patients (day 42 treatment difference, 5.7%; 95% CI, 2.1 to 9.4; p = 0.002). AZLI treatment improved mean FEV1 values for patients with differing lung disease severities and ages; the subgroups had comparable responses (Fig 2, right). At treatment end, changes in CFQ-R-Respiratory scores and FEV1 were modestly correlated (day 28 Pearson correlation coefficients: AZLI group, 0.32; placebo group, 0.32).

The adjusted mean relative change in FEV1 percent predicted values also increased for AZLI-treated patients and decreased for placebo-treated patients (day 28 treatment difference, 10.2%; 95% CI, 6.2 to 14.2; p < 0.001) and declined for both groups after treatment (day 42 treatment difference, 5.7%; 95% CI, 2.0 to 9.4; p = 0.003).

The adjusted mean sputum PA density decreased for AZLI-treated patients and remained near baseline for placebo-treated patients (day 28 treatment difference, − 1.453 log10 cfu/g; 95% CI, − 2.1 to − 0.8; p < 0.001) [Fig 2, left]. Two weeks after treatment (day 42), values were near baseline values for both treatment groups (p = 0.822).

There was a trend toward fewer hospitalized patients in the AZLI group (5%) than in the placebo group (14%; days 0 to 42; p = 0.064) and toward fewer mean hospitalization days (AZLI group, 0.5 days; placebo group, 1.5 days; p = 0.049). Weight increased 1.1% for the AZLI-treated group and 0.1% for the placebo-treated group (day 28: 95% CI, 0.33 to 1.69; p = 0.004).

The responses of AZLI-treated patients were significantly larger than those of placebo-treated patients for 6 of the 11 nonrespiratory CFQ-R scales; these scales included Eating, Emotional Functioning, Health Perceptions, Physical Functioning, Role Limitation/School Performance, and Vitality (Table 2).

Safety

The incidence of adverse events was similar for both groups during the AZLI/placebo treatment period, except “productive cough” was reported by significantly fewer AZLI-treated patients (10 patients; 12.5%) than placebo-treated patients (21 patients; 25%; p = 0.047) [Table 3]. Five patients were hospitalized during the treatment period (days 0 to 28); two patients due to respiratory symptoms (AZLI group, one patient; placebo group, one patient), two patients due to bowel obstruction (AZLI group, one patient; placebo group, one patient), and one patient due to umbilical hernia (placebo). Airway reactivity (a ≥ 15% decrease in FEV1 within 30 min after AZLI/placebo dosing at study visits) occurred in eight patients (AZLI group, three patients; placebo group, five patients); none withdrew for this reason. Clinically significant changes in vital signs or mean clinical laboratory values were not observed, except that AZLI-treated patients trended toward fewer shifts above the reference range for hematology variables; these were all markers of systemic inflammation. From day −14 to day 28, the percentage of patients with shifts above the reference range for WBC count were 11.4% and 5.3%, respectively; for neutrophil counts, 16.5% and 9.6%, respectively; for neutrophil percentage, 13.6% and 7.0%, respectively; and for platelets, 11.7% and 5.6%, respectively, for placebo-treated and AZLI-treated patients. There were no deaths during this study and no reports of anaphylaxis.

Table 3
Treatment-Emergent Adverse Events Reported by ≥ 5% Patients in Either Treatment Group During the AZLI/Placebo Treatment Period*

Clinical Pharmacology and Microbiology

Sputum and plasma aztreonam concentrations were measured (Table 4). Throughout the study, the aztreonam MIC50 and MIC90 values for all PA isolates from placebo-treated patients remained unchanged or decreased (Table 5). For AZLI-treated patients, a transient fourfold increase in MIC90 was observed (Table 5, day 14). The number of PA isolates with an aztreonam MIC > 8 μg/mL (ie, the parenteral breakpoint) and the proportion of patients with such isolates did not increase during AZLI treatment. Throughout the study, MIC50 and MIC90 values of the other antibiotics tested (tobramycin, gentamicin, amikacin, piperacillin, cefepime, meropenem, ceftazidime, ciprofloxacin, and ticarcillin/clavulanate) for all PA isolates from AZLI-treated patients remained unchanged (ie, changes of less than fourfold) or decreased, except for a possible persistent increase in the MIC90 value for ticarcillin/clavulanate (increase, 256 to > 256 μg/mL). There was no evidence for persistent increases in the isolation of Stenotrophomonas maltophilia, S aureus, or Achromobacter xylosoxidans resulting from treatment with AZLI (Table 6). B cepacia complex was not isolated.

Table 4
Aztreonam Concentrations in Sputum and Plasma for AZLI-Treated Patients
Table 5
MIC50 and MIC90 for All PA Isolates
Table 6
Treatment-Emergent Isolation of Other Organisms*

Discussion

Inhaled AZLI was administered at a dose of 75 mg three times daily for 28 days to patients with moderate-to-severe CF lung disease and PA airway infection. These patients were receiving lower levels of maintenance therapy than recommended in published treatment guidelines.11 Therapy with AZLI significantly improved respiratory symptoms and pulmonary function, and significantly decreased sputum PA density compared with placebo. AZLI was well tolerated; adverse events were generally consistent with symptoms of CF lung disease.

This was the first aerosolized antibiotic clinical study to use a PRO as the primary efficacy end point. Several studies10,23,24 from the past few years used CFQ-R scales as secondary efficacy end points. In this study, CFQ-R-Respiratory scores measured the benefits of AZLI therapy from the patient's perspective; the 9.7-point treatment response was larger than the 5-point MCID score previously determined for the CFQ-R-Respiratory Scale.13,21,25

Respiratory symptom improvements were confirmed by significant improvements in FEV1 and by the following adverse event measure: compared with placebo, AZLI treatment decreased the number of reports of “productive cough” by half. This demonstrates that patients with CF can reliably report their symptoms using a standardized measure and provides support for using PROs in clinical studies. However, the modest correlation between patient-reported changes in respiratory symptoms (CFQ-R-respiratory) and measured changes in lung function (FEV1) suggests that they are measuring different aspects of clinical efficacy; thus, a combination of patient-reported and physiologic measurements may be optimal.

In addition to respiratory symptoms, AZLI-treated patients reported improvements in disease-related symptoms involving eating, emotional and physical functioning, health perceptions, role limitations/school performance, and vitality. These results have particular relevance for patients with a chronic illness, who must adhere to complex, time-consuming medical regimens that affect their normal activities. Their perception of treatment benefit is likely to improve adherence to treatment regimens and influence their long-term health outcomes.26

CFQ-R-Respiratory scores and FEV1 increased for AZLI-treated patients from baseline to midtreatment, with little additional change to treatment end (day 28). However, treatment effects continued to be observed 2 weeks later. Adjusted mean PA density decreased throughout the 28-day AZLI treatment and returned to baseline values 2 weeks later. These results support the 28-day AZLI treatment period, which was extended from the 14-day treatment period utilized in a previous study.27

Only 15 patients (9.1%) in this study were children (ie, 6 to 12 years of age). For the analyses presented herein, they were combined with adolescent patients to give a group of 37 patients (22.6%) who were < 18 years of age. The mean improvement in the CFQ-R-Respiratory score was larger for these younger patients than for older patients. There was no apparent effect of age on improvement in lung function (FEV1).

Compared with patients in a previous 28-day AZLI study,10 patients in this study had received fewer courses of TIS during the previous year (mean number of courses, 1.8 vs 5.3, respectively), and at study entry fewer patients in this study were using dornase alfa (65% vs 85%, respectively) or azithromycin (0% [specified by entry criteria] vs 70%, respectively). Patients in both AZLI studies had comparable lung function (FEV1, ≥ 25% to ≤ 75% predicted values). The lower levels of maintenance therapy received by patients in the study described herein may reflect a number of factors, as follows: patient intolerance to available therapies; lack of clinical response to specific therapies; clinician and patient preferences; or the difficulty of obtaining TIS in some countries participating in the study (TIS is not commercially available in New Zealand or Australia). The treatment effects observed for these less intensively treated patients were larger than those observed in the previous AZLI study10 and approached those observed in the original TIS studies28,29 a decade ago. However, the population in the AZLI study described herein was on average, 8 years older, with a bacterial sputum density approximately 10-fold less, and baseline FEV1 percent predicted values 4 to 5% higher than those for the population enrolled in the original TIS studies.28 These baseline differences likely reflect the improved clinical management of CF that has been developed over the past decade.15 Patient compliance with TID dosing was high in the study described herein, it will also be interesting to assess patient compliance and treatment efficacy for the twice-a-day and three-times-a-day dosing groups in the ongoing 18-month AZLI study.

This study was designed to assess the short-term efficacy of AZLI and to provide a rationale for a long-term trial to evaluate its use as suppressive therapy in patients with chronic PA infection. Existing long-term therapies used in patients with CF have typically been assessed in controlled trials with a duration of 6 months.23,28,30 An open-label, 18-month clinical trial31 of AZLI (intermittent treatment every other month) is ongoing to address the efficacy and safety of long-term suppressive therapy.

The use of AZLI by clinicians will need to be guided by the results of the two completed phase III studies with regard to the patient's level of lung function, sputum microbiology, and tolerance of inhaled therapy and existing therapies. AZLI may provide an important new therapy for patients with CF who have moderate-to-severe lung disease. Since the improvement in respiratory symptoms and FEV1 can be easily monitored and measured in a short time period, a 28-day trial of therapy may be an appropriate method of assessing the value of AZLI therapy in an individual patient. Possible clinical strategies may include using AZLI in rotation with other inhaled antibiotics and/or in combination with other nonantibiotic therapies. However, further studies will be needed to define the appropriate strategy for incorporating AZLI use into the long-term treatment of chronic PA airway infection.

Acknowledgment:

We thank the patients and their families as well as the participating study sites, the site investigators, and the study research coordinators for the trial (see Appendix). We thank Kate Loughney for writing assistance in the preparation of this manuscript. Statistical analyses were performed by Kendle International and Gilead Sciences, Inc.

Abbreviations:

AZLI
aztreonam lysine for inhalation
CF
cystic fibrosis
CFQ-R
Cystic Fibrosis Questionnaire-revised
CFQ-R-Respiratory
Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Scale
CI
confidence interval
MCID
minimal clinically important difference
MIC
minimum inhibitory concentration
MIC50
minimum inhibitory concentration inhibiting the growth of 50% of Pseudomonas aeruginosa isolates
MIC90
minimum inhibitory concentration inhibiting the growth of 90% of Pseudomonas aeruginosa isolates
PA
Pseudomonas aeruginosa
PRO
patient-reported outcome
TIS
tobramycin inhalation solution

Appendix: Participating Study Sites, Site Investigators, and Study Research Coordinators for the AIR-CF1 Trial

Australia

Alfred Hospital, Melbourne, VIC; Site Investigator (SI): John Wilson; Research Coordinator (RC): Denise Clark.

Princess Margaret Hospital for Children, Perth, WA; SI: Tonia Douglas; RC: Charlotte Allen.

Royal Adelaide Hospital, Adelaide, SA; SI: Hugh Greville; RC: Kirsty Herewane.

Royal Children's Hospital, Herston, Brisbane, QLD; SI: Claire Wainwright; RC: Aaron Buckner.

Sir Charles Gairdner Hospital, Perth, WA; SI: Gerard Ryan; RC: Kerry Boughton.

The Children's Hospital at Westmead, Sydney, NSW; SI: Peter J. Cooper; RC: Karen McKay.

Westmead Hospital, Sydney, NSW; SI: Peter Middleton; RC: Karen Bovington.

Canada

Centre Hospitalier de l‘Université de Montreal (CHUM), Montreal, QC; SI: Yves Berthiaume; RC: Nadia Beaudoin.

Children's Hospital of Western Ontario, London, ON; SI: Brian Lyttle; RC: Anne-Marie Lyttle.

Queen Elizabeth II Health Sciences Centre, Halifax, NS; SI: Roger T. Michael; RC: Andrea Dale.

St. Paul's Hospital, Vancouver, BC; SI: Pearce Wilcox; RC: Georgina Lopez.

University of Alberta, Edmonton, AB; SI: Peter Zuberbuhler; RCs: Josette Salgado and Joan Tabak.

New Zealand

Greenlane Clinical Centre and Starship Children's Health Centre, Auckland; SI: John Kolbe; RC: Wendy Fergusson.

United States

Alamo Clinical Research Associates, San Antonio, TX; SI: Peter Fornos; RC: Terri Phillips.

Albany Medical College, Albany, NY; SI: Jonathan Rosen; RC: Katharine Mokhiber.

Baylor Research Institute, Dallas, TX; SI: Mark Millard; RC: Kim Waters.

Capital Allergy and Respiratory Disease Center, Sacramento, CA; SI: Bradley Chipps; RC: Bryce Autret.

Central Maine Pulmonary Associates, Lewiston, ME; SI: Ralph Harder; RC: Rachel Barry.

Children's Hospital Los Angeles, Los Angeles, CA; SI: Marlyn Woo; RC: Lynn Fukushima.

Children's Hospital of Orange County, Orange, CA; SI: Bruce Nickerson; RC: Luis Valdez.

Children's Hospital of Pittsburgh, Pittsburgh, PA; SI: Joseph Pilewski; RCs: Judy Fulton, Elizabeth Hartigan, and Sandra Hurban.

Childrens Lung Specialists, Las Vegas, NV; SI: Craig Nakamura; RC: Tara Brascia.

Children's Memorial Hospital and Northwestern University, Chicago, IL; SI: Susanna McColley; RC: Catherine Powers.

Cincinnati Children's Hospital Medical Center, Cincinnati, OH; SIs: Bruce Trapnell and Cori Daines; RC: Lorrie Duan.

Long Island Jewish Medical Center, New Hyde Park, NY; SI: Rubin Cohen; RC: Maryanne Gannon.

Louisiana State University Health Sciences Center, Shreveport, LA; SI: Kimberly Jones; RC: Antoinette Gardner.

Medical College of Georgia, Augusta, GA; SI: Margaret Guill; RC: Julie C. Hall.

Miller Children's Hospital and Long Beach Memorial Hospital, Long Beach, CA; SI: Terry Chin; RC: Mariam Ischander.

Naval Medical Center, Portsmouth, VA; SI: Rees Lee; RC: Adrienne Espinosa.

Nemours Children's Clinic, Orlando, FL; SI: Mark Weatherly; RC: Sondra Sadler.

Pediatric Breathing Disorders Clinic, Anchorage, AK; SI: Dion Roberts; RC: Vicki Roberts.

Pediatric Pulmonary Associates, Columbia, SC; SI: Daniel Brown; RC: Carolyn Turner.

Phoenix Children's Hospital, Phoenix, AZ; SI: Peggy Radford; RCs: Natalia Argel and Annette Szpiszar Gong.

Riley Hospital for Children, Indianapolis, IN; SI: Michelle Howenstine; RCs: Mary Blagburn and Delana Terrill.

St. Barnabas Healthcare System, Livingston, NJ; SI: Dorothy Bisberg; RC: Carol Epstein.

St. Louis University, St Louis, MO; SI: Ravi Nayak; RC: Jennifer Dizes.

State University of New York (SUNY) Upstate Medical University, Syracuse, NY; SI: Ran Anbar; RC: Donna Lindner.

Tulane University Health Sciences Center, New Orleans, LA; SI: Blesilda Quiniones; RC: Melanie Larrieu.

University of Alabama at Birmingham, Birmingham, AL; SI: JP Clancy; RC: Ginger Reeves.

University of Arkansas for Medical Sciences, Little Rock, AR; SI: Paula Anderson; RC Adam Taggart.

University of Florida Health Sciences Center, Gainesville, FL; SI: L. Terry Spencer; RC: Dawn Baker.

University of Iowa, Iowa City, IA; SI: Richard Ahrens; RC: Mary Teresi.

University of Michigan, Ann Arbor, MI; SI: Samya Nasr; RC: Ermee Sakmar.

University of Missouri, Columbia, MO; SI: Peter Konig; RC: Donna M. Smith.

University of North Carolina at Chapel Hill, Chapel Hill, NC; SI: George Z. Retsch-Bogart; RC: Carol Woody-Barlow.

University of Pennsylvania Health System, Philadelphia, PA; SI: Denis Hadjiliadis; RC: Barbara Finkel.

University of Utah, Salt Lake City, UT; SI: Theodore Liou; RC: Kristyn Packer.

University of Washington Medical Center, Seattle, WA; SI: Moira Aitken; RC: Sharon McNamara.

University of Wisconsin, Madison, WI; SI: James Runo; RC: Sharen Wilson.

University of Mississippi Medical Center, Jackson, MS; SI: Fadel Ruiz; RC: Kim Adcock.

Via Christi Regional Medical Center, St. Francis Campus, Wichita, KS; SI: Maria Riva; RC: Janet Messamore.

Virginia Commonwealth University, Richmond, VA; SI: Greg Elliott; RC: Juellisa Gadd.

Yale-New Haven Hospital, New Haven, CT; SI: John R. McArdle; RC: Kathryn Engle.

Footnotes

Funding/Support: This study was funded by Gilead Sciences, Inc, and by National Institutes of Health General Clinical Research Center grants M01 RR00188, M01 RR00037, M01 RR02172, M01 RR00043, M01 RR000489, M01 RR00034, M01 RR00039, M01 RR00750, M01 RR01066, M01 RR001070, M01 RR10733, M01 RR00070, M01 RR10710, M01 RR00069, M01 RR00827, M01 RR00082, M01 RR023940, M01 RR00042, M01 RR00400, and M01 RR00065.

Financial/nonfinancial disclosures: Dr. Retsch-Bogart received clinical research support as a site investigator conducting clinical trials from Corus Pharma (purchased by Gilead Sciences, Inc), Gilead Sciences, Inspire Pharmaceuticals, Genentech, Pathogenesis Corp, Boehringer-Ingelheim, and Cystic Fibrosis Foundation Therapeutics, Inc. Dr. Quittner was a consultant and served on an advisory board for Corus Pharma and Gilead Sciences. Dr. Montgomery is employed by Gilead Sciences and prior to this by its predecessor company, Corus Pharma, Inc. He is patent author on Aztreonam Lysine, and Gilead Sciences is patent holder. He holds equity interest in Gilead Sciences. Dr. Gibson received clinical research support as a site investigator conducting clinical trials from Corus Pharma, Gilead Sciences, Inspire Pharmaceuticals, and Cystic Fibrosis Foundation Therapeutics. He served on an advisory board for Genentech. Dr. McCoy received clinical research support as a site investigator conducting clinical trials from Corus Pharma, Gilead Sciences, Inspire Pharmaceuticals, and Genentech. Dr. Oermann received clinical research support as a site investigator conducting clinical trials from Corus Pharma and Gilead Sciences. Dr. Cooper received clinical research support as a site investigator for clinical trials sponsored by Corus Pharma and Gilead Sciences.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).

References

1. Cystic Fibrosis Foundation Patient Registry. 2005 Annual data report to the center directors. Bethesda, MD: Cystic Fibrosis Foundation; 2006.
2. Novartis. Prescribing information, TOBI: tobramycin inhalation solution, USP. [Accessed October 28, 2008]. Available at; http://www.pharma.us.novartis.com/product/pi/pdf/tobi.pdf.
3. Genentech. Prescribing information, Pulmozyme: dornase alfa. [Accessed October 28, 2008]. Available at: http://www.gene.com/gene/products/information/opportunistic/pulmozyme/insert.jsp.
4. Clement A, Tamalet A, Leroux E, et al. Long term effects of azithromycin in patients with cystic fibrosis: a double blind, placebo controlled trial. Thorax. 2006;61:895–902. [PMC free article] [PubMed]
5. Gibson RL, Burns JL, Ramsey BW. State of the art: pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med. 2003;168:918–951. [PubMed]
6. Riekert KA, Mogayzel PJ, Bilderback A, et al. Medication adherence among children, adolescents, and adults with CF [abstract] Pediatr Pulmonol. 2007;42:405. (abstract 563)
7. Gibson RL, Retsch-Bogart GZ, Oermann C, et al. Microbiology, safety and pharmacokinetics of aztreonam lysinate for inhalation in patients with cystic fibrosis. Pediatr Pulmonol. 2006;41:656–665. [PubMed]
8. Bristol-Myers Squibb Company. Prescribing information, Azactam: aztreonam injection. [Accessed October 28, 2008]. Available at: http://www.fda.gov/cder/foi/label/2002/50632slr011lbl.pdf.
9. Dietzsch HJ, Gottschalk B, Heyne K, et al. Cystic fibrosis: comparison of two mucolytic drugs for inhalation treatment (acetylcysteine and arginine hydrochloride) Pediatrics. 1975;55:96–100. [PubMed]
10. McCoy KS, Quittner AL, Oermann CM, et al. Inhaled aztreonam lysine is effective in intensively-treated patients with cystic fibrosis. Am J Respir Crit Care Med. 2008;178:921–928. [PMC free article] [PubMed]
11. Flume PA, O'Sullivan BP, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2007;176:957–969. [PubMed]
12. Henry B, Aussage P, Grosskopf C, et al. Development of the Cystic Fibrosis Questionnaire (CFQ) for assessing quality of life in pediatric and adult patients. Qual Life Res. 2003;12:63–76. [PubMed]
13. Quittner AL, Buu A, Messer MA, et al. Development and validation of the Cystic Fibrosis Questionnaire in the United States: a health-related quality-of-life measure for cystic fibrosis. Chest. 2005;128:2347–2354. [PubMed]
14. Modi AC, Quittner AL. Validation of a disease-specific measure of health-related quality of life for children with cystic fibrosis. J Pediatr Psychol. 2003;28:535–546. [PubMed]
15. US Food and Drug Administration. Draft guidance on patient-reported outcome measures. [Accessed October 28, 2008]. Available at: http://www.fda.gov/cder/guidance/5460dft.htm.
16. American Thoracic Society Committee on Diagnostic Standards for Non-Tuberculous Respiratory Diseases. Standardization of spirometry 1994 update. Am J Respir Crit Care Med. 1995;152:1107–1136. [PubMed]
17. Knudson RJ, Lebowitz MD, Holberg CJ, et al. Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis. 1983;127:725–734. [PubMed]
18. Bucholski A, Keller M, Balcke A, et al. In vitro performance of eFlow, an electronic inhaler for administration of a novel aztreonam formulation to CF patients. Pediatr Pulmonol [abstract] 2003;35(suppl):321. (abstract 392)
19. Guyatt GH. Making sense of quality-of-life data. Med Care. 2000;38(suppl):175–179. [PubMed]
20. Jaeschke R, Singer J, Guyatt GH. Measurement of health status: ascertaining the minimal clinically important difference. Control Clin Trials. 1989;10:407–415. [PubMed]
21. Quittner AL, McCoy K, Montgomery B. Inhaled antibiotics to treat stable patients with cystic fibrosis and Pseudomonas aeruginosa (PA): measuring patient perception of symptom improvement [abstract] Pediatr Pulmonol. 2007;42:301. (abstract 280)
22. Burns JL, Emerson J, Stapp JR, et al. Microbiology of sputum from patients at cystic fibrosis centers in the United States. Clin Infect Dis. 1998;27:158–163. [PubMed]
23. Elkins MR, Robinson M, Rose BR, et al. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med. 2006;354:229–240. [PubMed]
24. Donaldson SH, Bennett WD, Zeman KL, et al. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N Engl J Med. 2006;354:241–250. [PubMed]
25. Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc. 2007;4:378–386. [PMC free article] [PubMed]
26. Modi AC, Lim CS, Yu N, et al. Multi-method measurement of treatment adherence for children with cystic fibrosis and its relationship to health-related quality of life [abstract] Pediatr Pulmonol. 2005;40:371.
27. Retsch-Bogart GZ, Burns JL, Otto KL, et al. A phase 2 study of aztreonam lysine for inhalation to treat patients with cystic fibrosis and Pseudomonas aeruginosa infection. Pediatr Pulmonol. 2008;43:47–58. [PubMed]
28. Ramsey BW, Pepe MS, Quan JM, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl J Med. 1999;340:23–30. [PubMed]
29. Lamb HM, Goa KL. Drugs in disease management: management of patients with cystic fibrosis: defining the role of inhaled tobramycin. Dis Manage Health Outcomes. 1999;6:93–108.
30. Fuchs HJ, Borowitz DS, Christiansen DH, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med. 1994;331:637–642. [PubMed]
31. Oermann CM, McCoy KA, Retsch-Bogart GZ, et al. Effect of multiple Aztreonam Lysine for Inhalation (AZLI) cycles on disease-related endpoints and safety in patients with cystic fibrosis (CF) and Pseudomonas aeruginosa (PA): interim analysis of 12 month data [abstract] J Cystic Fib. 2008;7(suppl):S25. (abstract 100)

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