Inhaled antibiotics are considered standard of care for patients with cystic fibrosis (CF) who have chronic infection of the airways by Pseudomonas aeruginosa (Pa).^1-3 Antibiotic formulations have approved for inhalation by regulatory agencies, but this has not always been the case. Ad hoc use of antibiotics by inhalation were reported as early as the 1940s,⁴ but the first controlled study of inhaled antibiotics in CF patients did not appear in the literature until 1981,⁵ followed by a series of small studies.

The path to approved products started with the novel, off-label use of nebulized IV formulations, but it was the investment of the Cystic Fibrosis Foundation that spurred meaningful commercial investment in new CF drugs. The early industry approach was to repurpose existing drugs (eg, tobramycin) and to work with regulatory agencies on what would be required for marketing authorization.

Tobramycin was the first drug to undergo development as an inhaled formulation. In 1989 Dr. Arnold Smith et al⁶ observed that the pharmacokinetics of tobramycin clearance were unusual in patients with CF compared to that of other patients, primarily because CF sputum acted a reservoir for tobramycin. It was important that the drug was in the sputum, at the site of infection, but the sputum itself rendered the drug inactive. This observation led to the hypothesis that larger quantities of tobramycin, which could only be delivered by the inhaled route, could improve outcomes. Subsequent clinical trials demonstrated an increase in lung function (ie, forced expiratory volume in 1 second, FEV₁) during prolonged exposure to inhaled tobramycin, as long as three months. The further observation and cause for concern, however, was that the treatment selected for tobramycin-resistant Pa at the end of three months reverted to tobramycin susceptibility after follow up. The fact that the peak FEV₁ response at two weeks was sustained at four weeks but was somewhat less at eight weeks led to the decision for a shorter course of therapy, based on studies comparing four to eight weeks of treatment.⁷ There seemed to be little efficacy advantage for the longer treatment duration, which led to the intermittent (ie, 28 days on-28 days off) regimen for the pivotal phase 3 clinical trials⁸, under the belief that chronic intermittent use might reduce emergence of tobramycin resistance while retaining the improved pulmonary function for a longer period.

The development of inhaled tobramycin was contingent upon accepted clinical endpoints. Microbiological endpoints (ie, a reduction in bacterial density) were not considered acceptable surrogate endpoints, as they did not correlate well with how a patient feels, functions, or survives. Although there was skepticism about an improvement in FEV₁, that measure became the accepted primary endpoint. Pulmonary exacerbations, frequent events in the lives of CF patients yet requiring many more patients to power a study, initially became the secondary endpoint but were later seen to be of critical importance.

Since the approval of tobramycin solution for inhalation, there has been approval of additional inhaled antibiotics in the US, including aztreonam lysine and a powder formulation of tobramycin. The approval of these products was based upon a similar regimen used for tobramycin solution (ie, month on-month off). Since the approval of these inhaled antibiotics, a key question has arisen: Is the intermittent regimen the most effective, or would a chronic, daily regimen prove more effective?

The question is becoming of greater importance as the reported use of inhaled antibiotics has evolved over the last few years. Since the approval of inhaled aztreonam in 2009, there has been considerable change in the prevalence of patients receiving multiple antibiotic classes,⁹ suggesting more clinicians are adopting and prescribing a new, continuous treatment regimen, but one with alternating antibiotics. In 2009 nearly 13,000 patients were reported to be using inhaled antibiotics, of which approximately 86% were on monotherapy (ie, only one inhaled antibiotic), presumably following the indicated intermittent regimen. Just three years later, in 2012, nearly 14,000 patients on inhaled antibiotics, approximately 30%, were reportedly prescribed more than one antibiotic.

One might consider a continuous regimen of antibiotic therapy on clinical worsening of the patient despite regular use of the intermittent regimen. It has been known since the original trials that lung function declined during the period off inhaled antibiotics, and some patients may continue to suffer pulmonary exacerbations. Thus, keeping antibiotic pressure on the infected airways has become an accepted approach to treatment. A regimen of continuous inhaled antibiotics can take several forms. One could use continuous monotherapy — ie, no time off drug — or there could be a rotation of antibiotics, ie, continuous alternating therapy (CAT). Studies have provided some evidence that changing to a new antibiotic may yield further improvements in FEV₁.¹⁰ Further, as more inhaled agents become available, one could conceive of even more complex rotational regimens. The investigation of whether a CAT regimen is superior to the approved intermittent regimen presents potential challenges. The dosing of medications can be simplified into open label use of an approved product (every other month), while the between months would be a comparison of a second drug (approved or investigational) to placebo. Pragmatically, this may require use of more than one device, as the approved products are not administered through the same inhalation mechanisms. One might question whether every 28 days is the best duration for a rotating antibiotic schedule, but since the current approved duration is 28 days, it is most practical for the first test of regimens to follow that course.

The clinical endpoint of interest is also challenging. The motivation to change from the approved intermittent regimen to a CAT regimen is driven by perceived adverse outcomes, such as a drop in lung function or the occurrence of pulmonary exacerbations. The precedent for approval of an inhaled antibiotic has been a change in lung function, but given the early discomfort of regulatory agencies with this endpoint and the likelihood that there may be limited ability to further improve lung function on treatment with an alternate antibiotic, this is not a good choice. Thus a reduction in pulmonary exacerbations becomes an attractive primary endpoint that is relevant to patients as well as to regulatory agencies. This is the logic that led to the design of the CAT trial (NCT01641822), a study to investigate whether using a continuous, alternating therapy regimen of two antibiotics of different classes may reduce acute pulmonary exacerbations, maintain lung function, and control respiratory symptoms for patients with CF.

References
1. Döring G, et al. Treatment of lung infection in patients with cystic fibrosis: Current and future strategies. J Cyst Fibr. 2012;11:461-479.
2. Mogayzel et al. Cystic Fibrosis Pulmonary Guidelines: Chronic Medications for Maintenance of Lung Health. Am J Respir Crit Care Med. 2013;187:680-689.
3. Smyth AR, et al. European Cystic Fibrosis Society Standards of Care: Best Practice guidelines. J Cyst Fibr 2014; S23-S42.
4. Hodson et al. Aerosol carbenicillin and gentamicin treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis. Lancet. 1981 Nov 21;2(8256):1137-1139.
5. Mendelman et al. Aminoglycoside Penetration, Inactivation, and Efficacy in Cystic Fibrosis Sputum. Am Rev Respir Dis.1985;132:761-765.
6. AL Smith, BW Ramsey, DL Hedges, et al. Safety of aerosol tobramycin administration for 3 months to patients with cystic fibrosis. Pediatr Pulmonol. 1989;7:265–271.
7. Ramsey et al. Efficacy of aerosolized tobramycin in patients with cystic fibrosis. N Engl J Med. 1993;328:1740-1746.
8. Ramsey et al., Intermittent Administration of Inhaled Tobramycin in Patients with Cystic Fibrosis. N Engl J Med. 1999;340:23-30.
9. Dasenbrook EC., Konstan MW., VanDevanter DR. Association between the introduction of a new cystic fibrosis inhaled antibiotic class and change in prevalence of patients receiving multiple inhaled antibiotic classes. J Cyst Fibr. 2015;14:370-371.
10. McCoy et al. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med. 2008;178:921-928.

CLICK HERE to listen to eCysticFibrosis Review Program Director Dr. Peter Mogayzel discuss the design, findings and impact of the CAT trial with Dr. Patrick Flume of the Medical University of South Carolina.

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CLICK HERE to listen to Guest Author Dr. Patrick Flume of the Medical University of South Carolina discuss current inhaled antibiotic protocols at the Prince Charles Hospital in Queensland, Australia with Dr. Scott Bell.

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Click here to listen to Guest Author Dr. Patrick Flume of the Medical University of South Carolina discuss the CAT trial and its impact on antibiotic scheduling at Cincinnati Children's Hospital in Cincinnati Ohio with Dr. JP Clancy.

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Click here to listen to Guest Author Dr. Patrick Flume of the Medical University of South Carolina discuss the CAT trial and its impact on antibiotic scheduling at the Queens University Adult Cystic Fibrosis Center in Belfast Northern Ireland with Dr. Stuart Elborn.

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