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

Gibson, Ronald L.; Retsch‐Bogart, George; Oermann, Christopher M.; Milla, Carlos; Pilewski, Joseph M.; Daines, Cori; Ahrens, Richard C.; León, Kevin; Cohen, Morty; McNamara, Sharon; Callahan, Tracy L.; Márkus, Richard; Burns, Jane L.

doi:10.1002/ppul.20429

Cited by 104 publications

(120 citation statements)

References 19 publications

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“…Observed sputum concentrations demonstrate that no significant dose accumulation occurred after 1 week of treatment, this is consistent with results of the previous Phase 1b study. 12 Plasma concentrations were dose-dependent. Peak concentrations for the 75 and 225 mg doses were 79-and 33-fold lower than peak levels (54 mg/ml) observed after administration of a single 500 mg intravenous dose.…”

Section: Discussionmentioning

confidence: 96%

“…The specimens were processed and analyzed according to methods previously described. 12 Plasma samples were obtained immediately before dosing and 60 min after the start of dosing on Days 0 and 7. On Day 14, plasma samples were obtained at the start of the visit.…”

Section: Determination Of Aztreonam Concentrationmentioning

confidence: 99%

“…Analysis was performed as described for the preceding study. 12 Bronchodilator Use During the Trial Patients taking bronchodilators, either a long-acting formulation or a short acting agent as needed or once daily, continued their use as prescribed. Patients taking shortacting bronchodilators twice-daily or more were instructed to refrain from using them for 6 hr before study visits.…”

Section: Determination Of Aztreonam Concentrationmentioning

confidence: 99%

“…A previous Phase 1b, placebo-controlled, double-blind, single dose escalation study in adolescent and adult patients with CF 12 reported a good safety profile and effective airway concentrations when doses between 75 mg (1 ml) and 225 mg (3 ml) were delivered with the eFlow 1 electronic nebulizer. Based on these results, we conducted a Phase 2 study to evaluate the safety, tolerability and efficacy of 75 and 225 mg AZLI doses administered twice daily for 14 days in patients with CF and mild to moderate obstructive lung disease.…”

Section: Introductionmentioning

confidence: 99%

“…10,11 Unlike tobramycin, the activity of aztreonam is not inhibited in the presence of sputum from CF patients. 12 Aztreonam has been administered intravenously in the treatment of CF pulmonary exacerbations. [13][14][15] The parenteral formulation of aztreonam (Azactam 1 ) contains arginine, which has been shown to cause airway inflammation after chronic inhaled administration to CF patients.…”

Section: Introductionmentioning

confidence: 99%

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

Retsch‐Bogart¹,

Burns

Otto³

et al. 2007

Pediatric Pulmonology

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100

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Summary. 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 1 Electronic Nebulizer (Pari Innovative Manufacturers, Inc., Midlothian, VA). Patients were 13 years and older with FEV 1 ! 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 FEV 1 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 FEV 1 at Day 14, demonstrated no statistically significant difference. Post hoc analysis demonstrated significant increase in FEV 1 at Day 7 for the subset of patients with baseline FEV 1 < 75% predicted in the 225 mg AZLI group. Bronchodilator use was associated with greater improvement in FEV 1 , 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

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Section: Discussionmentioning

confidence: 96%

Section: Determination Of Aztreonam Concentrationmentioning

confidence: 99%

Section: Determination Of Aztreonam Concentrationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Retsch‐Bogart¹,

Burns

Otto³

et al. 2007

Pediatric Pulmonology

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100

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Medicinal Chemistry of β‐Lactam Antibiotics

Testero

Llarrull

Fisher

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The β‐lactam class of antibacterials is a cornerstone of human health. For nearly eight decades, their unparalleled clinical efficacy and clinical safety have made the β‐lactam class preeminent in the treatment of bacterial infection. The relatively brief period in human history during which the β‐lactams have exerted this benefit is a period characterized by continuous medicinal chemistry innovation, seen visibly in the progression from the penicillins to the complex ensemble of β‐lactams (now including also cephalosporins, monobactams, and carbapenems) used in the clinic. The key force behind this innovation is the progressive evolution by bacteria of resistance mechanisms. Today, highly resistant bacteria challenge the way medicinal chemists contemplate the creative alteration of β‐lactam structures, the way the pharmaceutical industry develops β‐lactams (and other antibacterial) structures, and the way the medical community uses antibacterials. This article gives a concise summary of the history of the β‐lactams. Its emphasis is recent structural innovation with respect to the β‐lactams, and with respect to structurally related classes that act to preserve the clinical activity of the β‐lactams through inhibition of bacterial β‐lactam‐hydrolyzing, and thus β‐lactam‐deactivating, enzymes. We integrate these chemistry advances with new biological discoveries with respect to the bactericidal mechanism of the β‐lactams and with respect to bacterial resistance mechanisms. The combination of these perspectives is a foundational perspective to guide the medicinal chemistry future of the β‐lactams.

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Nebulised anti-pseudomonal antibiotics for cystic fibrosis

Ryan

Mukhopadhyay

Singh

2003

Cochrane Database of Systematic Reviews

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

Abstract: These data support the continued development of AI for treatment of pulmonary infections in patients with CF.

Cited by 104 publications

References 19 publications

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

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

Medicinal Chemistry of β‐Lactam Antibiotics

Nebulised anti-pseudomonal antibiotics for cystic fibrosis

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