Christopher M. Oermann

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).

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, FEV1 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. Pediatr Pulmonol. 2010;45:1121–1134.

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

BACKGROUND Open-label, parallel-group, international trial comparing aztreonam for inhalation solution (AZLI) and tobramycin nebulizer solution (TNS) for cystic fibrosis patients with airway Pseudomonas aeruginosa. METHODS 273 patients (≥ 6 years); randomized to three 28-day courses (AZLI 75 mg [three-times/day] or TNS 300 mg [twice/day]); 28 off-days separated each course. RESULTS 268 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 28 days off-treatment); lung function improvements were comparable regardless of whether patients had received TNS or AZLI in the preceding comparative period. CONCLUSIONS AZLI demonstrated statistical superiority in lung function and a reduction in acute pulmonary exacerbations compared to TNS over 3 treatment courses (ClinicalTrials.gov: NCT00757237).

Immunogenicity of a new purified fusion protein vaccine to respiratory syncytial virus: A multi-center trial in children with cystic fibrosis

A third generation, purified fusion protein (PFP-3) vaccine was developed to prevent severe respiratory syncytial virus (RSV) disease in high-risk groups. A phase II, multi-center, adjuvant-controlled trial was performed in RSV seropositive children with cystic fibrosis (CF); 151 received the adjuvant-control and 143 received the vaccine. Details of the vaccine-induced immune response are presented. At enrollment, RSV-specific, serum antibodies were comparable between both groups. A highly sensitive and specific serum antibody vaccine profile was established for the PFP-3 vaccine. At post-vaccination and end-of-study, RSV-specific, neutralizing antibody (Nt Ab) and binding antibody (Bd Ab) to the fusion (F) protein were significantly higher in PFP-3 vaccinees. After 28 days post-vaccination, Nt Ab and Bd Ab to F protein titers declined slowly at rates of 0.23 and 0.37 log2 per month, respectively. The PFP-3 vaccine-induced a robust immune response that lasted throughout the RSV season.

Safety and Preliminary Clinical Activity of a Novel Pancreatic Enzyme Preparation in Pancreatic Insufficient Cystic Fibrosis Patients

Objectives: Currently available pancreatic enzyme products are crude porcine products with few data available regarding their efficacy, safety, and manufacture. We conducted a phase 1 study of a novel pancreatic enzyme product, TheraCLEC-Total (TCT), a proprietary formulation of microbial-derived lipase, protease, and amylase, to determine its safety and preliminary efficacy in cystic fibrosis. Methods: We conducted an open-label, dose-ranging study in 23 subjects diagnosed with pancreatic insufficiency with cystic fibrosis. The subjects received TCT containing lipase dose of 100, 500, 1000, 2500, or 5000 USP U/kg per meal with each meal or snack for 3 days. The clinical and laboratory parameters and adverse events (AEs) were monitored. Results: There were no serious AEs. Most AEs were mild, although gastrointestinal complaints were common. TCT increased the coefficient of fat and nitrogen absorption in all groups except in the low-dose group. At the other dosing levels, the mean coefficient of fat and nitrogen absorption increases were 19.1% ± 24.9% and 17.8% ± 13.6%, respectively, whereas the mean stool weight decreased by 517 ± 362 g. Conclusions: TCT was well tolerated in this short-term exposure study. The preliminary efficacy data demonstrate lipase and protease activity with little difference seen with lipase doses greater than 500 USP U/kg per meal. These data support a larger randomized phase 2 trial.

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 patients 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.

Lessons learned from a randomized trial of airway secretion clearance techniques in cystic fibrosis

Airway secretion clearance therapies are a cornerstone of cystic fibrosis care, however longitudinal comparative studies are rare. Our objectives were to compare three therapies [postural drainage and percussion: (postural drainage), flutter device (FD), and high frequency chest wall oscillation: (vest)], by studying (1) change in pulmonary function; (2) time to need for intravenous (IV) antibiotics, (3) use of pulmonary therapies, (4) adherence to treatment, (5) treatment satisfaction, and (6) quality of life.

Severe necrotizing pneumonitis in a child with Mycoplasma pneumoniae infection

Lower respiratory tract illness due to Mycoplasma pneumoniae is typically mild and self‐limited. There are, however, numerous reports of serious and life‐threatening cases of mycoplasma pneumonia in adults. We present a case involving a 4‐year‐old girl with severe mycoplasma infection and necrotizing pneumonitis requiring lobectomy. A detailed pathological report is provided. Pediatr. Pulmonol. 1997;24:61–65.

Pharmacokinetics of Ibuprofen in Patients with Cystic Fibrosis

Study Objectives. To determine the pharmacokinetic disposition of high doses of ibuprofen in patients with cystic fibrosis (CF), and to evaluate the reliability of intrapatient dosage adjustments to achieve recommended peak ibuprofen plasma concentrations.

Inhaled morphine to relieve dyspnea in advanced cystic fibrosis lung disease

Inhaled morphine has been used to treat dyspnea in a variety of clinical settings. There are, however, no reports of its use in treating patients with end‐stage lung disease due to cystic fibrosis (CF). We report on the use of inhaled morphine sulfate in a 13‐year‐old boy with CF, advanced lung disease, and acute respiratory failure. Therapy was effective in reducing his subjective feeling of air hunger and improving his BORG score. His sole significant adverse effect was headache after 2 days of treatment at 4‐hourly intervals. Pediatr Pulmonol. 2000; 30:257–259.