Optimal airway antimicrobial therapy for cystic fibrosis: the role of inhaled aztreonam lysine

Figures & data

Box 1. Drug summary.

Drug name (generic)	European Union (EU): Aztreonam lysine 75 mg powder and solvent for nebulizer solution (AZLI) Canada, USA: Aztreonam for inhalation solution Australia: Aztreonam for inhalation
Phase	Marketed in the EU, Canada, Australia, and the USA
Indication	EU*: Indicated for the suppressive therapy of chronic pulmonary infections due to Pseudomonas aeruginosa in patients with cystic fibrosis (CF) aged 18 years and older. The primary support for this indication is based on two single 28-day course, placebo-controlled studies. The data to support the sustainability of the observed short-term benefit over subsequent courses of treatment are limited. Consideration should be given to official guidance on the appropriate use of antibacterial agents. Multiple-course, controlled efficacy data are not yet available. Additional courses, beyond the initial 28-day course, should be considered only at the discretion of the physician. If additional courses are prescribed, a minimum of 28 days without AZLI is recommended
	Canada*: Indicated for the management of CF patients with chronic pulmonary P. aeruginosa infections. Demonstration of longer-term safety and efficacy of AZLI is limited to uncontrolled, open-label clinical trial data obtained over nine cycles of therapy. Safety and efficacy have not been demonstrated in patients with FEV1 < 25 or > 75% predicted or in patients colonized with Burkholderia cepacia complex. Sputum culture and susceptibility testing performed periodically will provide information on changing microbial flora and the possible emergence of bacterial resistance
	Australia: Indicated for control of Gram-negative bacteria, particularly P. aeruginosa, in the respiratory tract of patients with CF. The primary support for this indication is based on two single 28-day course, placebo-controlled studies. The data to support the sustainability of the observed short-term benefit over subsequent courses of treatment are limited
	USA: Indicated to improve respiratory symptoms in CF patients with P. aeruginosa. Safety and effectiveness have not been established in pediatric patients below the age of 7 years, patients with FEV1 < 25 or > 75% predicted, or patients colonized with Burkholderia cepacia. To reduce the development of drug-resistant bacteria and maintain the effectiveness of AZLI and other antibacterial drugs, AZLI should be used only to treat patients with CF known to have P. aeruginosa in the lungs
	*Conditionally approved in Canada and the EU, pending the results of studies to verify clinical benefit
Pharmacology description/mechanism of action	Monobactam bactericidal antibiotic; time-dependent killing of sensitive Gram-negative bacteria
Route of administration	Inhaled; 75-mg dose; administered 3 times/day
Chemical structure	(Z)-2-[[[(2-amino-4-thiazolyl)[[(2S,3S)-2-methyl-4-oxo-1- sulfo-3-azetidinyl]carbamoyl] methylene]amino]oxy]-2-methylpropionic acid
Pivotal trials	AIR-CF1, AIR-CF2, AIR-CF3

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Table 1. Summary of Phase II and Phase III AZLI clinical trials.

Clinical trial [Ref]	Study population	Treatment regimen	Primary efficacy end point	Comments
CP-AI-003 [49]	105 CF patients (USA); ≥ 13 years old; P. aeruginosa airway infection; FEV1 ≥ 40% predicted; no antipseudomonal or macrolide antibiotics within 56 days of study drug dosing	14 days' double-blind treatment; 75 mg and 225 mg AZLI vs placebo, twice daily; patients were followed for 14 days after treatment (to day 28)	Change in pulmonary function from day 0 to day 14	This Phase II trial provided sufficient safety and efficacy data to warrant continued investigation of AZLI. Design features of Phase III trials resulting from this study: • 75-mg dose was selected for further study based on an apparent increase in dose-related respiratory adverse events • A 28-day course was proposed • 3 times daily dosing was proposed • All patients were to be treated with a bronchodilator before administration of AZLI • Enrollment would include patients with FEV1 ≤ 75 and ≥ 25% predicted values
AIR-CF1 [46]	164 CF patients (USA, Canada, Australia, New Zealand); ≥ 6 years old; P. aeruginosa airway infection; FEV1 ≥ 25 to ≤ 75% predicted; no antipseudomonal or macrolide antibiotics within 14 days of study drug dosing	28 days' double-blind treatment; 75 mg AZLI vs placebo; 3 times daily; patients were followed for 14 days after treatment (to day 42)	Change in respiratory symptoms as measured by the CFQ-R Respiratory Symptoms Scale	TIS use in the previous 12 months averaged 1.8 courses for patients in this trial. TIS was not commercially available in Australia and New Zealand; average use was 2.3 courses for US and Canadian patients in the preceding 12 months. Thus patients in this trial seemed to be receiving less maintenance CF therapy than recommended at present in the USA [20]
AIR-CF2 [47]	211 CF patients (USA); ≥ 6 years old; P. aeruginosa airway infection; FEV1 ≥ 25 to ≤ 75% predicted; must have received ≥ 3 courses of TIS in previous 12 months	28 days' double-blind treatment; 75 mg AZLI vs placebo; 2 or 3 times daily; patients received open-label TIS for 28 days before study drug treatment and were followed for 56 days after treatment (to day 84)	Time to need for i.v. or additional inhaled antipseudomonal antibiotics following start of blinded study drug treatment	Mean TIS use in the preceding 12 months was 5.3 courses; thus patients in this trial seemed to be receiving maintenance CF therapy in line with current US recommendations [20]
AIR-CF3 [50-53]	Open-label, follow-on trial; included 274 patients from AIR-CF1 or AIR-CF2	Up to nine 28-day courses; 75 mg AZLI alternating with 28-day treatment-free periods; dosing 2 (85 patients) or 3 times (189 patients) daily, continue regimen from original trial	Safety of repeated exposure to AZLI	Provides long-term data on 9 courses of AZLI (28 days on/28 days off treatment) in conjunction with any other therapeutic regimens for CF prescribed by each patient's health care provider(s). Three times daily dosing seemed more efficacious than twice daily dosing

AZLI: Aztreonam lysine 75 mg powder and solvent for nebulizer solution; CF: Cystic fibrosis; CFQ-R: Cystic fibrosis questionnaire-revised; FEV₁: Forced expiratory volume in 1 sec; i.v.: Intravenous; TIS: Tobramycin inhalation solution.

Figure 1. AIR-CF1 and AIR-CF2: change from baseline values for CFQ-R Respiratory Symptoms Scores, FEV₁ (L), FEV₁% predicted and Pseudomonas aeruginosa density in sputum.

Table 2. Summary of CFQ-R results in Phase III AZLI trials: change from baseline at day 28.

CFQ-R Scale*		AIR-CF1^¶		AIR-CF2^¶
		Placebo (n = 84)	AZLI t.i.d. (n = 80)	Placebo (n = 76)	AZLI b.i.d. + t.i.d. (n = 135)
Respiratory Symptoms^‡	Adj. mean change	-2.63	7.08	-0.66	4.34
	Treatment difference (p value)^§		9.71 (< 0.001)		5.01 (0.020)
Physical Functioning	Adj. mean change	-6.86	2.32	-3.28	0.61
	Treatment difference (p value)^§		9.18 (0.001)		3.88 (0.074)
Vitality	Adj. mean change	-4.35	3.64	-1.34	0.69
	Treatment difference (p value)^§		7.99 (0.005)		2.03 (0.370)
Emotional Functioning	Adj. mean change	-1.30	3.90	0.03	0.94
	Treatment difference (p value)^§		5.20 (0.005)		0.91 (0.539)
Eating Disturbances	Adj. mean change	-4.74	3.64	-1.83	-0.55
	Treatment difference (p value)^§		8.37 (< 0.001)		1.28 (0.470)
Health Perceptions	Adj. mean change	-4.83	4.99	0.23	-0.51
	Treatment difference (p value)^§		9.82 (< 0.001)		-0.74 (0.719)
Role Limitations/School Performance	Adj. mean change	-4.23	2.13	-2.18	1.63
	Treatment difference (p value)^§		6.36 (0.014)		3.81 (0.027)

*Responses to child and teen/adult versions of the CFQ-R were combined for analyses.

^‡The CFQ-R Respiratory Symptoms Scale was the primary efficacy end point in AIR-CF1 and an important secondary end point in AIR-CF2.

^§Treatment differences and p values are reported as parametric ANCOVA (analysis of covariance). Models include baseline values as predictors; disease severity is also included in the model and for AIR-CF1.

^¶No significant findings in either study for CFQ-R Treatment Burden, Social Functioning, Body Image, Weight Disturbances or Digestive Symptoms scales.

AZLI: Aztreonam lysine 75 mg powder and solvent for nebulizer solution; b.i.d.: Dosed twice daily; CFQ-R: Cystic Fibrosis Questionnaire – Revised; t.i.d.: Dosed three times daily.

Figure 2. AIR-CF3: effect of multiple AZLI cycles on change from baseline values for CFQ-R Respiratory Symptoms scores, FEV₁ (L), FEV₁% predicted and Pseudomonas aeruginosa density in sputum.

Table 3. Adverse drug reactions adjusted for study duration: comparison of pooled AZLI placebo-controlled trials, AIR-CF1 and AIR-CF2, and the open-label AZLI trial, AIR-CF3.

Preferred term^‡,#	No. of occurrences per patient-month
	Pooled AIR-CF1 and AIR-CF2 placebo-controlled trials^*		AIR-CF3 open-label trial^*
	Placebo (n = 160) (275 patient-months)	AZLI^§ (n = 215) (442 patient-months)	AZLI^§ (n = 274) (4128 patient-months)
Cough	0.356	0.387	0.279
Chest discomfort	0.040	0.059	0.032
Wheezing	0.065	0.072	0.029
Nasal congestion	0.073	0.097	0.045
Rhinorrhoea^¶	0.040	0.041	0.034
Pharyngolaryngeal pain	0.062	0.068	0.051
Pyrexia	0.036	0.088	0.055
Rash	0.011	0.009	0.007
Vomiting^#	0.025	0.032	0.021
Abdominal pain^#	0.029	0.041	0.013

^*The numbers of adverse drug reactions per patient-month are shown. Patient-months were calculated by summing study duration (days) for all patients and dividing by 28.

^‡Adverse events were coded with the Medical Dictionary for Regulatory Activities, Version 8.0.

^§Includes patients receiving AZLI two or three times daily.

^¶Not included in the list of common adverse reactions in the US prescribing information [34].

^#Not included in the list of common adverse reactions in the European summary of product characteristics, the Canadian product monograph, or the Australian product information [32,33]. Events of crackles lung, dysphonia, dyspnea, productive cough, throat irritation, hemoptysis, respiratory tract congestion, arthralgia, and headache were also considered by study investigators as possibly or probably related to study medication, and were included in the list of the most common adverse reactions in the Canadian product monograph [32].

AZLI: Aztreonam lysine 75 mg powder and solvent for nebulizer solution.

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