Retsch-Bogart,G.Z., Quittner,A.L., Gibson,R.L., Oermann,C.Met al. Efficacy and safety of inhaled aztreonam lysine for airway pseudomonas in cystic fibrosis. 2009. Chest 135:1223-1232. (For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)

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Oermann,C.M., Retsch-Bogart,G.Z., Quittner,A.L., Gibson,R.L et al. An 18-month study of the safety and efficacy of repeated courses of inhaled aztreonam lysine in cystic fibrosis. 2010. Pediatr. Pulmonol. (epub ahead of print) (For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)

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The management of chronic Pseudomonas aeruginosa (PA) airway infection in CF is one of the major challenges facing clinicians who care for these patients. The use of inhaled antibiotics on a cycling schedule has become a key part of the management of CF lung disease, and until recently only one approved therapy was available: tobramycin inhalation solution (TOBI®; Novartis). However, an alternative inhaled antibiotic, aztreonam lysine (AZLI; Cayston®; Gilead Sciences), received FDA approval earlier this year. Reviewed here are 2 recently published studies that contributed to the approval of this new therapy. In the first study (AIR-CF1), Retsch-Bogart et al conducted a randomized, double-blind, placebo-controlled study of AZLI (75 mg, TID via eFlow® Electronic Nebulizer; PARI Innovative Manufacturers) for 28 days in patients with moderate to severe CF lung disease and chronic PA infection.⁽¹⁾ The 164 enrolled patients were cared for at 53 CF centers in Australia, Canada, New Zealand, and the United States. Subjects were >6 years of age and had an FEV₁ between 25-75% of predicted (inclusive). Important exclusion criteria included infection with Burkholderia cepacia complex and use of azithromycin, hypertonic saline, or other antipseudomonal antibiotics. The primary efficacy outcome of this study was the change in respiratory symptoms, as indicated by the CFQ-R Respiratory Symptom scale. In the second study (AIR-CF3), Oermann et al conducted an 18-month open-label extension study to evaluate the long-term safety and efficacy of AZLI.⁽²⁾ The 274 patients entering into this study had previously been enrolled either in AIR-CF1⁽¹⁾ or an earlier study (AIR-CF2),⁽³⁾ which demonstrated a delayed time to need additional antibiotic interventions after AZLI. In this open-label extension study, subjects continued with their previously assigned BID or TID dosing schedule during treatment months, with treatment occurring every other month. In contrast to AIR-CF1, azithromycin and hypertonic saline use was allowed in AIR-CF3. Although no formal hypothesis testing was performed, the longitudinal effects on lung function, CFQ-R Respiratory Symptom scale, sputum PA density, and other endpoints were described.

In AIR-CF1, mean subject age was 29.6 years (77.4% > 18 years) with a mean baseline FEV₁ of 54.6%. Baseline therapy use included rhDNase (65%) and ~1.7 courses of inhaled tobramycin solution in the prior year. With regard to the primary outcome, a 9.7 point difference in the CFQ-R Respiratory scale was noted between treatment groups. Of note, the magnitude of this difference is well above the minimal clinically important difference (MCID) of 4.⁽⁴⁾ A similar treatment effect was noted in those with moderate (FEV₁ >50-75% of predicted) or severe (FEV₁ 25-50% of predicted) lung disease, though younger patients (<18 years) appeared to have a larger improvement in respiratory symptoms. A significant treatment difference for FEV₁ (10.3%; p<0.001) was also noted, with similar improvement in the young vs. older age strata, and amongst those with moderate and severely reduced lung function. Other positive trends included fewer hospitalizations (5% vs. 14%; p = 0.064); fewer hospitalization days (0.5 vs. 1.5 days; p = 0.049); improved weight (1.1 vs. 0.1%; p = 0.004); and improvements in other CFQ-R domains (Eating, Emotional Functioning; Health Perceptions; Physical Functioning, Role Limitation/School Performance; and Vitality). Comparison of adverse event (AE) rates revealed less “productive cough” in AZLI-treated patients, and no other concerning safety signals. In AIR-CF3, 71.2% of patients completed the study, with a similar discontinuation rate between BID and TID treated patients. Only a small percentage of patients discontinued due to drug intolerance, study-related AE’s, or noncompliance. By examining changes in FEV₁ and the CFQ-R Respiratory Symptom scale, it is clear that improvements in both parameters occurred with each treatment cycle, but that the improvements rapidly waned by the end of each “off” cycle. A somewhat larger treatment effect was noted in the TID group than in the BID group, perhaps most notably with regard to the CFQ-R Respiratory Symptom scale. The relative improvement in FEV₁ (% predicted) was 4.2-8.0% in the TID group, and 1.2-5.1% in the BID group. The decrease in PA density was <1 log10 cfu/g with each treatment cycle in both groups. Transient increases in the MIC90, but not the MIC50, were noted in both treatment groups. Adherence, according to empty vial counts, was 88.0% and 92.0% in the TID and BID groups, respectively.

As the result of these (and other) studies, there is little doubt that AZLI can lead to meaningful improvements in respiratory symptoms and lung function, while extending the time before needing additional anti-pseudomonal therapies after 28 days of therapy⁽³⁾. Perhaps not surprisingly, patients receiving fewer therapies at baseline in AIR-CF1 had larger clinical responses than patients already receiving more aggressive care in the previously published AIR-CF2 trial. In AIR-CF3, we are left to interpret data without an accompanying control group. This is particularly problematic when examining AE data. However, the presented data in AIR-CF3 does support an ongoing benefit over 18 months from AZLI, and a retrospective comparison to case matched controls in the CFF Registry receiving standard of care therapy also revealed a 28% lower risk of hospitalization (p=0.020).⁽⁵⁾ Reassuringly, only a relatively minor change in aztreonam resistance patterns was observed (transient increase in MIC90) during the 18 month period of study.

Given the availability of multiple treatment options, one would ideally like to be able to compare their safety and efficacy. However, given the influence that other therapies and care practices have on antibiotic responses, comparisons to results with inhaled tobramycin more than a decade earlier are extremely problematic. Further, even a head-to-head comparison would likely only be interpretable if both groups were naive to their assigned therapy or, at the very least, had a similar prior exposure. Therefore, it is likely that the choice clinicians and patients make when choosing between inhaled tobramycin and aztreonam will likely revolve around factors other than evidence of superior efficacy. Rather, if tolerability is similar in a given patient, factors such time of treatment, preference for the appropriate delivery device, cost, and concerns regarding cumulative toxicity and the development of resistance will likely drive decision making. Clearly, the short treatment times achieved with use of the eFlow® nebulizer will likely be very desirable to many patients, and may have contributed to the high adherence rate observed in the long-term AIR-CF3 study. A larger, unanswered question is how the use of inhaled antibiotics should be personalized for individual patients. Should every patient with chronic PA infection and abnormal FEV₁ values be treated chronically with inhaled antibiotics, likely for decades, or can other factors (e.g. exacerbation frequency, prior rate of lung function decline) be incorporated into a decision-making process that extracts the most benefit out of the antibiotic over the lifetime of the patient? Clearly, as the number of treatment options grows, the complexity of these decisions will continue to increase, as will the expectations for improved outcomes.

Commentary References

1.	Retsch-Bogart,G.Z., Quittner,A.L., Gibson,R.L., Oermann,C.M., et al. Efficacy and safety of inhaled aztreonam lysine for airway Pseudomonas aeruginosa in cystic fibrosis. 2009. Chest 135:1223-1232.
2.	Oermann,C.M., Retsch-Bogart,G.Z., Quittner,A.L., Gibson,R.L., et al. An 18-month study of the safety and efficacy of repeated courses of inhaled aztreonam lysine in cystic fibrosis. 2010. Pediatr. Pulmonol.
3.	McCoy,K.S., Quittner,A.L., Oermann,C.M., Gibson,R.L., et al. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. 2008. Am. J. Respir. Crit Care Med. 178:921-928.
4.	Quittner,A.L., Modi,A.C., Wainwright,C., Otto,K., et al. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. 2009. Chest 135:1610-1618.
5.	Montgomery,A.B., Lewis,S., Higuchi,K., Marshall,B., and Oermann,C. Hospitalization risk of current standard of care (SOC) vs. aztreonam for inhalation solution (AZLI) in patients with cysti fibrosis (CF). 2009. Am J Respir Crit Care Med 179:A1188 (Abstr.)