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Role of Inhalational Aztreonam Lysine in Lower Airway Infections in Cystic Fibrosis: An Updated Literature Review

Cystic fibrosis (CF) is an inherited disorder most prevalent in the Caucasian population, characterized by a functional abnormality of the transmembrane conductance regulator protein that leads to a wide array of complications, including chronic lung infections. Pseudomonas aeruginosa (PA) is a frequently acquired microbe in CF patients and is associated with deterioration in pulmonary function and increased mortality. Inhaled anti-infective agents are an established curative therapy for CF airway infections, especially with chronic PA lung disease. Amongst them, aztreonam lysine for inhalation (AZLI) is an aerosolized monobactam antibiotic aztreonam, approved for use in CF patients nearly a decade ago. This literature review aims to explore studies based on the efficacy, safety, and tolerability of AZLI use in CF patients with pulmonary infections. We searched for all the relevant articles present in PubMed, Google Scholar, Cochrane Library, EMBASE, ClinicalTrials.gov, and Journal of Cystic Fibrosis for our data collection from 2000 to 2020. The use of AZLI has substantially improved lung function, respiratory symptoms, and remarkably reduced sputum PA density in CF patients, thereby improving the patient's overall quality of life. The adverse effects reported were compatible with CF lung disease. Hence, inhalational therapy with AZLI is highly efficacious and safe in the management of chronic airway infections. More clinical trials need to be conducted in the future to assess its long-term clinical benefits and adverse events as well as to explore the role of AZLI in the setting of acute lung infections.


Introduction And Background
Cystic fibrosis (CF) is the life-limiting autosomal recessive inherited condition most prevalent in the Caucasian population, with an incidence of 1 in 2000 to 3000 live births [1]. In the United States, the median predicted survival for CF patients is 47.4 years (95% CI, 44.2-50.3) for those who were born in 2018, according to the CF Foundation 2018 Registry Report [1]. CF is caused by the abnormal transport of chloride ions, resulting in thick, viscous mucus production within the lungs, which leads to impairment of pulmonary function [1].
In patients with CF, lower airway infections continue to be a leading cause of increased morbidity and mortality [2]. Pseudomonas aeruginosa (PA) is a frequently encountered pathogen affecting CF airways, leading to steeper deterioration in lung function [3]. Early acquisition of PA infections is with nonmucoid environmental strains that show a good response to antibiotic treatment [4]. Over time, chronic infections are caused by the mucoid phenotype, which is associated with deterioration in lung function, resistance to antibiotic treatment, and worsening quality of life [5,6]. Several treatment options are used to eradicate the pathogen. Amongst them, inhaled anti-infective agents are used to mitigate early and chronic PA infections [5,6].
Inhalational antibiotics are the standard of care in the treatment of chronic P. aeruginosa infections because of their minimal systemic effects, good tolerability, and minimal drug-to-drug interaction [7]. Aztreonam lysine for inhalation (AZLI) is a novel aerosolized lyophilized formulation of the monobactam antibiotic aztreonam and has antipseudomonal activity, whereas lysine salt prevents airway inflammation [7]. The US Food and Drug Association (FDA) approved this formulation for use in cystic fibrosis patients in 2010 [8][9][10].
In clinical practice, we advise AZLI in CF patients who cannot tolerate inhaled tobramycin, or have worsening lung function, during gestation when aminoglycosides are relatively contraindicated and by the patient's choice [11]. It is given through a nebulizer at a dosage of 75 mg inhalation thrice a day, cycling between 28 days on and 28 days off the drug [11].
Several clinical trials were conducted in both children and adults to assess the safety, efficacy, and 1 2, 3, 4 1 1 1

Quality of life
The Cystic Fibrosis Questionnaire-Revised (CFQ-R) is a disease-specific, validated measure of health-related quality of life (HRQoL) for CF patients, which has several different domains depending upon age [13]. Several studies have shown favorable outcomes from AZLI use. A phase 3, randomized, placebo-controlled trial (AIR-CF1), was performed on 164 subjects who were treated with 75 mg of AZLI thrice a day for 28 days or placebo [7]. The adjusted mean CFQ-R respiratory scores improved for AZLI-treated subjects than for placebo (difference for 28 days, 9.7 points; p<0.001) [7]. The study also found superior changes for 6/11 nonrespiratory CFQ-R scores [7].
In an 18-month open-label study, Oermann et al., reported greater improvement on the CFQ-R Respiratory Symptom scale in 274 patients with each course and received up to nine courses of AZLI 75 mg (28 days on/28 days off) twice or thrice a day [14]. In a recent study, Frost et al. designed an open-label randomized cross-over study in 16 participants with CF [15]. In this pilot study, subjects were given AZLI for 14 days along with intravenous colistin (AZLI+IV) or standard dual intravenous therapy (IV+IV) during pulmonary exacerbations requiring hospitalization and showed a change in CFQ-R Respiratory Domain in participants treated with AZLI+IV (83.3% vs. 43.8%, p=0.03) [15]. This report on the promising role of AZLI during acute pulmonary exacerbation showed a new pathway, and more studies are warranted for its application [15]. In 2008, McCoy et al. published a phase 3 study (AIR-CF2), which was carried out between 2005 and 2006 in 56 CF centers in the United States [16]. In this AIR-CF2 trial, 211 patients were randomly treated with AZLI/placebo for 28 days (twice or thrice a day), and CFQ-R respiratory scores were estimated as secondary endpoints [16]. Mean CFQ-R respiratory scores showed a notable improvement (5.01 points, P = 0.02) [16]. The studies related to favorable outcomes on quality of life are shown in Table 1.
observed an improvement in sputum PA density after nine "28" day cycles of AZLI [14]. Frost et al. observed no remarkable change in sputum bacterial density in CF patients between two treatment groups, i.e. (AZLI + IV) and (IV + IV) during acute pulmonary exacerbations [15]. In addition, PA bacterial resistance was enhanced after treatment with double intravenous therapy (IV+IV) compared to AZLI plus intravenous antibiotic (AZLI+IV) [15].  [17]. After applying inclusion and exclusion criteria, 157 patients were treated with either AZLI (75 mg) or placebo thrice a day, and subjects were monitored on day 14, day 28 (completion of treatment), and day 42 [17]. One of the secondary endpoints was a change in sputum PA density from the baseline, which was assessed on day 28 from the baseline [17]. This trial yielded statistically significant change for adjusted mean log10 sputum PA colony-forming units (−1.2 log10 CFU/g; AZLI = −1.4; placebo = −0.14; p=0.016), thereby favoring AZLI [17].  [19]. This study depicted that 89.1% of patients were free of PA infection after 28 days and 58.2% remained culture-negative throughout the follow-up visits after the completion of treatment [19]. The studies related to changes in sputum PA density are shown in Table 2.

Changes in FEV1 from baseline
Recurrent airway infections have detrimental effects on lung function, but the introduction of AZLI has addressed this issue and improved outcomes effectively, as evident from several clinical trials and observational studies [7,14,15,17]. Retsch-Bogart et al. demonstrated remarkable improvement in respiratory symptoms in patients with moderate to severe lung diseases at baseline and no prior use of antipseudomonal antibiotics [7]. On completion of treatment, the mean adjusted forced expiratory volume in one second (FEV1) increased (95% CI, 6.3 to 14.3; p < 0.001) and remained above baseline after treatment [7]. In 2010, Oermann et al. published a clinical trial that showed a sustained improvement in FEV1 from baseline over nine on/off cycles of AZLI [14]. In a recent phase 4 study published in 2019, Frost et al. conducted a randomized, controlled cross-over, pilot study to assess the role of AZLI during acute pulmonary exacerbations compared to standard intravenous therapy [15]. Sixteen subjects were randomized between two treatment groups: AZLI with an intravenous antibiotic, i.e., colistin (AZLI+IV), and standard double intravenous therapy (IV+IV) [15]. This trial revealed significant changes in FEV1 from baseline in the AZLI+IV treatment group compared to double IV therapy (IV+IV) (p=0.002) [15]. In a phase 3 clinical trial, McCoy et al. showed the adjusted mean difference for percent predicted FEV1 (ppFEV1) between AZLI and the placebo-treated group was 6.3% (p=0.001) [16].
In a phase 3b (AIR-CF4) clinical trial, Wainwright et al. also observed a mean relative change in FEV1% predicted at 2.7% (p=0.021) in a 12-month clinical trial [17]. Moreover, AZLI showed promising results in patients with baseline FEV1 less than 90% predicted (p=0.032) in comparison to FEV1 more than 90% predicted (p=0.302) [17]. In a retrospective cohort study published in 2017, Morton et al. assembled study data from two years before (t-2) and after (t+2) starting AZLI and depicted changes in FEV1 were arrested with continual treatment [20]. Plant et al. designed a study on inhaled aztreonam lysine (AZLI), and data were collected from multiple centers in Ireland and the UK [21]. This trial divided 24 months into four time zones of six-month intervals each [21]: zero to six months (P1), six to twelve months (P2) prior to initiation of AZLI and zero to six months (T1), six to twelve months (T2) after starting AZLI, and FEV1 was monitored across all time zones [21]. After analyzing the data, it was revealed that the median FEV1 predicted had worsened from P2 to P1 (p=0.001) but improved notably from P1 to T1 after the initiation of AZLI (p=0.03) [21].  [22]. The articles related to changes in FEV1 from baseline are shown in Table 3.

Safety and tolerability
AZLI is a safe and well-tolerated inhaled anti-infective agent. Various studies worked on the safety profile of AZLI and found that it has adverse effects as well, apart from its clinical efficacy [7,14,16,17]. Retsch-Bogart et al. monitored the safety and tolerability of AZLI in a phase 3 clinical trial [7]. The study revealed a productive cough in the AZLI-treated group compared to the placebo (p=0.047) [7]. The reactive airway was observed in three patients and five patients for AZLI and placebo-treated groups, respectively [7]. No notable changes were found in the laboratory profile and vitals, and also, mortality or anaphylactic reactions were not reported [7]. In an 18-month phase 3 clinical trial (AIR-CF3), Oermann et al. also monitored the long-term safety profile of AZLI, including adverse effects, CF aggravating respiratory and non-respiratory symptoms, laboratory levels, and vitals of patients [14]. The most frequent adverse effect was attributed to respiratory symptoms (cough 89.4%; productive cough 80.3%) [14]. Serious adverse effects of AZLI were 44.7% for the twice-a-day group and 52.4% for the thrice-a-day group [14]. Non-respiratory symptoms were anorexia, fever, fatigue, and headache [14]. Moreover, no remarkable changes were observed in vitals and laboratory variables [14]. McCoy et al. also assessed the safety of AZLI in a randomized, placebo-controlled trial in 211 subjects in multiple CF centers [16]. The study observed that adverse events were not statistically remarkable in all three treatment groups (AZLI twice-daily dosage BID; thrice daily dosage TID; and placebo) [16]. Out of 211 subjects, nine needed hospitalization (seven with pulmonary exacerbation, one with hyponatremia, and one with intestinal obstruction) [16]. Hence, AZLI-treated groups were welltolerated and adverse effects were compatible with CF respiratory symptoms [16]. Wainwright [17]. The studies showing the safety and tolerability of AZLI are shown in Table 4. Trial showed that adverse events were compatible with respiratory symptoms. There was no remarkable change in vitals and laboratory profile and no death was observed.
Oermann et al. [14] 2005- This study showed that cough was the most common adverse effect observed in AZLItreated group compared to placebo.

Hospitalization rates
Retsch-Bogart et al. also demonstrated that hospitalization had lessened in the AZLI-treated group compared to the placebo (5% versus 14%), though it was not statistically remarkable (p = 0.064) [7]. In the AIR-CF3 clinical trial, Oermann et al. showed a reduction in hospitalization in CF patients with AZLI use [14]. The most frequent cause of hospitalization is the emergence of lower respiratory tract infections [14]. The total hospitalization rate per patient year was 0.897, while the total respiratory hospitalization rate per patient year was 0.793 [14]. McCoy et al. monitored hospitalization data from admission to discharge using an electronic case report form from day zero to day 84 [16]. It showed no significant difference in time to the first hospitalization in CF patients between the AZLI-treated group and the placebo group [16]. The mean number of hospitalization days was 0.5 (placebo-treated group) and 0.9 (AZLI-treated group), respectively [16].
Plant et al. also showed a significant change in hospitalization after the initiation of AZLI [21]. Hospital bed days were reduced from 15.0 to 12.6 (p=0.05) [21]. In a retrospective case-control study (AIR-CF3), Montgomery et al. revealed a notable reduction in hospitalization risk in CF patients with AZLI use compared to standard-of-care (SOC) therapy (p=0.020) [23]. The rate of hospitalization per patient year was 0.91 for the AZLI group and 1.26 for the SOC therapy group [23]. The AZLI-treated group had a 28% lower risk of hospitalization compared to SOC [23]. Studies related to hospitalization rates are shown in Table 5.

AZLI in pediatric CF patients
Various phase 3 and phase 4 clinical trials demonstrated the efficacy and safety of AZLI among pediatric CF patients, which are discussed below [7,14,16,17,19,24]. Studies showed an increase in the percent predicted in FEV1 in children over six years [7,16]. Also, CF patients experienced an improvement in CFQ-R RSS scores, a reduction in sputum PA density, and fewer respiratory adverse events were observed [7,16]. Wainwright  open-label phase 2 clinical trial in pediatric patients aged three months to eighteen years [19]. It showed that 89.1% of CF patients were PA(-) after four weeks of AZLI therapy and 75.2% after eight weeks [19]. Clinical trials conducted in pediatric CF patients are shown in Table 6.

Conclusions
This review signifies that AZLI is an effective and well-tolerated inhalational anti-infective agent in CF patients with chronic PA infections. Cyclic therapy of AZLI (28 days on/28 days off) has a promising role in preserving lung function, reducing bacterial density in sputum, improving patients' life expectancy, and reducing hospitalisation rate, thereby enhancing the health quality of CF patients. Despite all the progress, more studies are warranted for this therapy to find out the long-term adverse effects, its clinical benefits in the long run with a larger sample size and extensive duration of follow-ups, and its safety as well as efficacy in infancy. It is also necessary to monitor the emergence of PA resistance over time to prevent eventual reinfection.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.