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Mechanism of Action

Aztreonam is an antibacterial drug.

Pharmacokinetics

Sputum Concentrations

Sputum aztreonam concentrations exhibited considerable variability between patients receiving CAYSTON (aztreonam for inhalation solution) (75 mg) in clinical trials. The mean sputum concentration 10 minutes following the first dose of CAYSTON (aztreonam for inhalation solution) (n = 195 patients with CF) was 726 mcg/g.   Mean sputum concentrations of aztreonam in patients receiving CAYSTON (aztreonam for inhalation solution) 3 times a day for 28 days were 984 mcg/g, 793 mcg/g, and 715 mcg/g 10 minutes after dose administration on Days 0, 14, and 28, respectively, indicating no accumulation of aztreonam in sputum.

Plasma Concentrations

Plasma aztreonam concentrations exhibited considerable variability between patients receiving CAYSTON (aztreonam for inhalation solution) (75 mg) in the clinical trials. The mean plasma concentration one hour following the first dose of CAYSTON (aztreonam for inhalation solution) (at approximately the peak plasma concentration) was 0.59 mcg/mL.  Mean peak plasma concentrations in patients receiving CAYSTON (aztreonam for inhalation solution) 3 times a day for 28 days were 0.55 mcg/mL, 0.67 mcg/mL, and 0.65 mcg/mL on Days 0, 14, and 28, respectively, indicating no systemic accumulation of aztreonam.  In contrast, the serum concentration of aztreonam following administration of aztreonam for injection (500 mg) is approximately 54 mcg/mL.

Absorption

Evaluation of plasma and urine aztreonam concentrations following administration of CAYSTON indicates low systemic absorption of aztreonam. Approximately 10% of the total CAYSTON (aztreonam for inhalation solution) dose is excreted in the urine as unchanged drug, as compared to 60–65% following intravenous administration of aztreonam for injection.

Distribution

The protein binding of aztreonam in serum is approximately 56% and is independent of dose.

Metabolism

Following intramuscular administration of aztreonam for injection 500 mg every 8 hours for 7 days, approximately 6% of the dose was excreted as a microbiologically inactive open β-lactam ring hydrolysis product in an 8-hour urine collection on the last day of multiple dosing.

Excretion

The elimination half-life of aztreonam from plasma is approximately 2.1 hours following administration of CAYSTON to adult patients with CF, similar to what has been reported for aztreonam for injection. Approximately 10% of the total CAYSTON (aztreonam for inhalation solution) dose is excreted in the urine as unchanged drug.  Systemically absorbed aztreonam is eliminated about equally by active tubular secretion and glomerular filtration. Following administration of a single intravenous dose of radiolabeled aztreonam for injection, about 12% of the dose was recovered in the feces. 

Microbiology

Mechanism of Action

Aztreonam exhibits activity in vitro against Gram-negative aerobic pathogens including P. aeruginosa. Aztreonam binds to penicillin­binding proteins of susceptible bacteria, which leads to inhibition of bacterial cell wall synthesis and death of the cell. Aztreonam activity is not decreased in the presence of CF lung secretions. 

Susceptibility Testing

A single sputum sample from a patient with CF may contain multiple morphotypes of P. aeruginosa and each morphotype may have a different level of in vitro susceptibility to aztreonam.  There are no in vitro susceptibility test interpretive criteria for isolates of  P. aeruginosa obtained from the sputum of CF patients.¹ 

Development of Resistance

No changes in the susceptibility of P. aeruginosa to aztreonam were observed following a 28-day course of CAYSTON (aztreonam for inhalation solution) in the placebo­controlled trials.

Cross-Resistance

No cross-resistance to other classes of antibiotics, including aminoglycosides, quinolones, and beta-lactams, was observed following a 28-day course of CAYSTON (aztreonam for inhalation solution) in the Phase 3 placebo­controlled trials or in an open-label follow-on trial of up to nine 28-day courses of 75 mg CAYSTON (aztreonam for inhalation solution) 3 times a day. 

Other

No trends in the treatment-emergent isolation of other bacterial respiratory pathogens (Burkholderia cepacia, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Staphylococcus aureus) were observed in clinical trials. There was a slight increase in the isolation of Candida spp. following up to nine 28-day courses of CAYSTON (aztreonam for inhalation solution) therapy.

Clinical Studies

CAYSTON (aztreonam for inhalation solution) was evaluated over a period of 28 days of treatment in a randomized, double-blind, placebo-controlled, multicenter trial that enrolled patients with CF and P. aeruginosa. This trial was designed to evaluate improvement in respiratory symptoms.  Patients 7 years of age and older and with FEV₁ of 25% to 75% predicted were enrolled. All patients received CAYSTON (aztreonam for inhalation solution) or placebo on an outpatient basis administered with the Altera Nebulizer System.  All patients were required to take a dose of an inhaled bronchodilator (beta-agonist) prior to taking a dose of CAYSTON (aztreonam for inhalation solution) or placebo.  Patients were receiving standard care for CF, including drugs for obstructive airway diseases.

The trial enrolled 164 patients with CF and P. aeruginosa. The mean age was 30 years, and the mean baseline FEV₁ % predicted was 55%; 43% were females and 96% were Caucasian.  These patients were randomized in a 1:1 ratio to receive either CAYSTON (aztreonam for inhalation solution) (75 mg) or volume-matched placebo administered by inhalation 3 times a day for 28 days. Patients were required to have been off antibiotics for at least 28 days before treatment with study drug.  The primary efficacy endpoint was improvement in respiratory symptoms on the last day of treatment with CAYSTON (aztreonam for inhalation solution) or placebo. Respiratory symptoms were also assessed two weeks after the completion of treatment with CAYSTON (aztreonam for inhalation solution) or placebo. Changes in respiratory symptoms were assessed using a questionnaire that asks patients to report on symptoms like cough, wheezing, and sputum production.  

Improvement in respiratory symptoms was noted for CAYSTON (aztreonam for inhalation solution) ­treated patients relative to placebo-treated patients on the last day of drug treatment.  Statistically significant improvements were seen in both adult and pediatric patients, but were substantially smaller in adult patients. Two weeks after completion of treatment, a difference in respiratory symptoms between treatment groups was still present, though the difference was smaller.  

Pulmonary function, as measured by FEV₁ (L), increased from baseline in patients treated with CAYSTON (aztreonam for inhalation solution) (see Figure 1). The treatment difference at Day 28 between CAYSTON (aztreonam for inhalation solution) -treated and placebo-treated patients for percent change in FEV₁ (L) was statistically significant at 10% (95% CI: 6%, 14%). Improvements in FEV₁ were comparable between adult and pediatric patients. Two weeks after completion of drug treatment, the difference in FEV₁  between CAYSTON (aztreonam for inhalation solution) and placebo groups had decreased to 6% (95% CI: 2%, 9%).

Figure 1: Adjusted Mean Percent Change in FEV₁ from Baseline to Study End (Days 0-42).

REFERENCES

1.         Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Eighth Edition; Approved Standard.  CLSI Document M7-A8. CLSI, Wayne, PA  19087. January, 2009.

Last reviewed on RxList: 3/11/2010
This monograph has been modified to include the generic and brand name in many instances.