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

Assael, B.M.; Pressler, Tacjana; Bilton, Diana; Fayon, Michaël; Fischer, Rainald; Chiron, R.; Larosa, M.; Knoop, Christiane; McElvaney, Noel G.; Lewis, Sandra A; Bresnik, Mark; Montgomery, A. Bruce; Oermann, Christopher M.

doi:10.1016/j.jcf.2012.07.006

Cited by 123 publications

(117 citation statements)

References 15 publications

(15 reference statements)

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“…To evaluate whether the magnitude of the model-predicted improvement in FEV 1 % predicted due to LAI was consistent with the magnitude of effect observed for patients with CF receiving other antibacterial agents, the results of four clinical studies in which patients with CF received treatment with either 112 mg of tobramycin inhalation powder twice daily or 75 mg of inhaled aztreonam lysine thrice daily were assessed (14)(15)(16)(17). Given that the baseline characteristics for the average patient who received treatment with LAI (i.e., 22 years of age with a BMI of 20 kg/m 2 and a baseline FEV 1 % predicted of 66%) were similar to those described in the other four studies (i.e., patients who were 25 to 29 years of age with a BMI of 20 to 21 kg/m 2 and a baseline FEV 1 % predicted of 52% to 55%), such comparisons for improvement in the FEV 1 % predicted among agents were considered appropriate.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Pharmacokinetics and Pharmacodynamics of Liposomal Amikacin for Inhalation in Cystic Fibrosis Patients with Chronic Pseudomonal Infections Using Data from Two Phase 2 Clinical Studies

Okusanya

Bhavnani

Hammel

et al. 2014

Antimicrob Agents Chemother

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The pharmacokinetic-pharmacodynamic (PK-PD) relationships between serum exposure measures of liposomal amikacin for inhalation (LAI) and the change in pulmonary function test (PFT) measures and number of CFU from baseline were evaluated in cystic fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa. A dose of 70, 140, 280, or 560 mg of LAI or placebo was administered to CF patients once daily for 28 days. PFTs and sputum samples for microbiology were assessed on days 7, 14, 21, 28, 35 (for log 10 CFU), and 56 (for PFTs). Serum, urine, and sputum samples were collected for PK evaluation. The relationships between efficacy endpoints (relative change in forced expiratory volume in 1 s [FEV 1 {expressed in liters}] and FEV 1 % predicted and the absolute change in log 10 CFU of P. aeruginosa from baseline) and exposure measures (dose, day 1 area under the curve [AUC], dose/MIC ratio, and day 1 AUC/MIC ratio) and baseline MIC value were assessed. The serum and urine PK data were best fit by a 3-compartment model (lung, serum, and urine) with linear clearance and interoccasional variation on total and renal clearance. Significant univariable relationships between dose or day 1 AUC and the relative change in PFT measures (P < 0.017) or the absolute change in log 10 CFU from baseline (P < 0.037) on the study days were identified. Repeated-measures mixed-effects models, which showed dose-and AUC-related improvements for each efficacy endpoint (P < 0.041), predicted the observed data well. The increases in the relative change in FEV 1 and FEV 1 % predicted of 11% and 9.9%, respectively, and a 1.23-log 10 CFU reduction per 560 mg of LAI estimated on day 7 were comparable to the observed increases of 10.7% and 10.3%, respectively, and a 1.24-log 10 CFU reduction on the same day. The model-estimated PFT effects were predicted to be sustained to day 28. An additional 0.451-log 10 CFU reduction (P ‫؍‬ 0.022) was estimated on day 14 relative to day 7, with a persistence of effect predicted to day 35.

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Section: Discussionmentioning

confidence: 99%

Evaluation of the Pharmacokinetics and Pharmacodynamics of Liposomal Amikacin for Inhalation in Cystic Fibrosis Patients with Chronic Pseudomonal Infections Using Data from Two Phase 2 Clinical Studies

Okusanya

Bhavnani

Hammel

et al. 2014

Antimicrob Agents Chemother

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“…The response to aerosolized tobramycin, as assessed by change in spirometry, becomes attenuated after extended exposure, a phenomenon that is not explained by selection of bacterial populations with decreased in vitro tobramycin susceptibilities 7,8 . It is likely that a similar attenuation of efficacy will occur for other inhaled antimicrobials with extended exposure 9 . In addition some patients are unable to tolerate particular inhaled antibiotic formulations 10,11 while others may find an inhaled therapy an excessive treatment burden resulting in poor adherence 12 .…”

Section: Introductionmentioning

confidence: 94%

A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients

Flume

VanDevanter

Morgan

et al. 2016

Journal of Cystic Fibrosis

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“…Noninferiority studies have shown that it is comparable, if not superior, to TIS in nontreatment-naive individuals with respect to increases in lung function (69). When used in trials for patients with CF with chronic B. cepacia complex infection, however, inhaled aztreonam did not result in any statistically significant improvement in FEV 1 or decreases in sputum bacterial density compared with placebo (70).…”

Section: Ats Seminarsmentioning

confidence: 99%

Antibiotic Management of Lung Infections in Cystic Fibrosis. I. The Microbiome, Methicillin-Resistant Staphylococcus aureus, Gram-Negative Bacteria, and Multiple Infections

et al. 2014

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Despite significant advances in treatment strategies targeting the underlying defect in cystic fibrosis (CF), airway infection remains an important cause of lung disease. In this two-part series, we review recent evidence related to the complexity of CF airway infection, explore data suggesting the relevance of individual microbial species, and discuss current and future treatment options. In Part I, the evidence with respect to the spectrum of bacteria present in the CF airway, known as the lung microbiome is discussed. Subsequently, the current approach to treat methicillin-resistant Staphylococcus aureus, gram-negative bacteria, as well as multiple coinfections is reviewed. Newer molecular techniques have demonstrated that the airway microbiome consists of a large number of microbes, and the balance between microbes, rather than the mere presence of a single species, may be relevant for disease pathophysiology. A better understanding of this complex environment could help define optimal treatment regimens that target pathogens without affecting others. Although relevance of these organisms is unclear, the pathologic consequences of methicillin-resistant S. aureus infection in patients with CF have been recently determined. New strategies for eradication and treatment of both acute and chronic infections are discussed. Pseudomonas aeruginosa plays a prominent role in CF lung disease, but many other nonfermenting gram-negative bacteria are also found in the CF airway. Many new inhaled antibiotics specifically targeting P. aeruginosa have become available with the hope that they will improve the quality of life for patients. Part I concludes with a discussion of how best to treat patients with multiple coinfections.

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

Abstract: AZLI demonstrated statistical superiority in lung function and a reduction in acute pulmonary exacerbations compared to TNS over 3 treatment courses (ClinicalTrials.gov: NCT00757237).

Cited by 123 publications

References 15 publications

Evaluation of the Pharmacokinetics and Pharmacodynamics of Liposomal Amikacin for Inhalation in Cystic Fibrosis Patients with Chronic Pseudomonal Infections Using Data from Two Phase 2 Clinical Studies

Evaluation of the Pharmacokinetics and Pharmacodynamics of Liposomal Amikacin for Inhalation in Cystic Fibrosis Patients with Chronic Pseudomonal Infections Using Data from Two Phase 2 Clinical Studies

A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients

Antibiotic Management of Lung Infections in Cystic Fibrosis. I. The Microbiome, Methicillin-Resistant Staphylococcus aureus, Gram-Negative Bacteria, and Multiple Infections

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