Inhaled antibiotics in Cystic Fibrosis (CF) and non-CF bronchiectasis.

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Inhaled Antibiotics in Cystic Fibrosis (CF) and Non-CF Bronchiectasis David W. Reid, MD1,2

Scott C. Bell, MD1,3

1 Department of Thoracic Medicine, The Prince Charles Hospital,

Brisbane, Australia 2 Lung Inflammation and Infection Group, QIMR Berghofer Medical Research Institute, Brisbane, Australia 3 Lung Bacteria Group, QIMR Berghofer Medical Research Institute, Brisbane, Australia

Address for correspondence Scott C. Bell, MD, Department of Thoracic Medicine, The Prince Charles Hospital, Rode Road, Chermside, 4032, Brisbane, Australia (e-mail: [email protected]).

Semin Respir Crit Care Med 2015;36:267–286.

Abstract

Keywords

► ► ► ► ► ►

antibiotics nebulized inhaled cystic fibrosis non-CF bronchiectasis Pseudomonas aeruginosa

Bronchiectasis is a pathological diagnosis describing dilatation of the airways and is characterized by chronic lung sepsis. Bronchiectasis has multiple etiologies, but is usually considered in terms of whether it is due to the genetic disorder cystic fibrosis (CF) or secondary to other causes (non-CF bronchiectasis, NCFB). Inhaled antibiotics are used in bronchiectasis to suppress bacterial pathogens and reduce long-term lung function decline. The majority of the literature on inhaled antibiotics comes from studies on CF where the dominant bacterial pathogen in the airway is usually Pseudomonas aeruginosa. Thus, most aerosolized antibiotic regimens target this bacterium, but the emergence of molecular diagnostic methods has questioned this approach and more tailored strategies may need to be considered in CF based on the community composition of the lung microbiome. Similarly, the lung microbiome in NCFB has been found to be a complex polymicrobial one and the current practice of employing the same inhaled antibiotic regimes as are used in CF may no longer be appropriate in many patients. In this article, the use of inhaled antibiotics in CF and NCFB is considered in the light of improved understanding of the lung microbiome and why more tailored therapy may be needed based on molecular identification of the microbial pathogens present. The evidence for the use of currently available inhaled antibiotics and advances in inhaled drug packaging and delivery devices are discussed. Finally, the urgent need for prospective randomized clinical trials in CF and NCFB is highlighted and areas for future research identified.

Bronchiectasis is a pathological diagnosis and the original description of chronic dilatation of the bronchi and bronchioles with accompanying airway infection holds true today.1 The classic paradigm is of an initial airway injury in bronchiectasis that leads to a chain of events in susceptible individuals involving infiltration of the airways by activated neutrophils and CD4þ T cells, which contributes to progressive dilatation of the airway wall and failure of structural integrity.2,3 The normal function of the protective mucociliary escalator is lost and microbial pathogens become established with stimulation of a robust innate immune response

Issue Theme Cystic Fibrosis and Non-Cystic Fibrosis Bronchiectasis; Guest Editor: Andrew M. Jones, MD, FRCP

that contributes to further airway destruction. Bronchiectasis has multiple etiologies, but for the purposes of this review of inhaled antibiotic therapies, we have divided bronchiectasis into that secondary to the genetic disorder, cystic fibrosis (CF), and non-CF bronchiectasis (NCFB) causes. Our rationale for undertaking the review in this way is that the majority of the literature on inhaled antibiotic therapy in bronchiectasis comes from studies on CF, and there has been, until recently, an assumption that a similar approach to bacterial infection in the airway in NCFB will be beneficial. In this article, we compare and contrast airway immunopathology and

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DOI http://dx.doi.org/ 10.1055/s-0035-1547346. ISSN 1069-3424.

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George T.P. Tay, MBChB1

Inhaled Antibiotics in CF and Non-CF Bronchiectasis

Tay et al.

microbiology in CF and NCFB and discuss this in the context of currently available and emerging inhaled antibiotic therapies.

Etiology of Bronchiectasis Earlier articles in this review series have discussed the etiology and epidemiology of bronchiectasis in depth and we direct the reader to these sections for a more comprehensive overview. Briefly, CF is a systemic disease, but the lung manifestations are the most severe and remain the predominant cause of premature death. More than 1,900 CFTR gene mutations have been described and there is a degree of heterogeneity in the clinical, including severity of the lung disease phenotype.4 NCFB has multiple etiologies, including genetic conditions such as the immotile cilia syndrome and common variable immunodeficiency, but the majority of cases of NCFB are not genetic in origin with the prevalence (and etiology) of NCFB differing both between and within countries. A major contributor is poor socioeconomic status with some populations, including indigenous peoples being disproportionately affected in developed countries such as the United States, Canada, and Australia.5,6

Airway Pathology in CF and Non-CF Bronchiectasis While the gross pathological changes in the lung are fundamentally the same in CF and NCFB, the rate of progression and extent of the changes are quite different. This suggests that key differences exist in the pathogenesis of lung disease in CF and NCFB, with implications for the effectiveness of therapeutic strategies that need to be considered. Despite this, the similarities in respiratory manifestations including profile of airway bacterial pathogens make it an attractive proposition to apply the same interventions in NCFB that have been successfully trialed in CF. However, the interaction between host immune response and resident pathogens (bacterial, fungal, or viral) and the intrinsic reparative mechanisms of the airway are likely to be different in CF and NCFB, which may impact on the relative clinical effectiveness of inhaled antibiotics in CF compared with NCFB. The basic pathological processes that lead to airway injury and remodeling are common to both diseases with persistent bacterial infection in the airway being the key driver of a chronic inflammatory response characterized by an influx of activated polymorph nuclear leukocytes (PMN).2 The airway epithelium bears the brunt of the initial insult, and as disease progresses the airway submucosa becomes chronically infiltrated by lymphocytes that coordinate the transit of PMN into the airway lumen.7–9 The production of proteolytic enzymes and harmful free radicals by activated PMN leads to airway injury with fibrosis of the airway, thickening of the basement membrane, mucous gland hypertrophy, goblet cell hyperplasia, neo-angiogenesis, and degradation of cartilage.1,2,10,11 The immunopathology of airway inflammation and remodeling in CF and NCFB is not fully understood, predominantly because of ethical considerations in CF where airway biopsies are not without risk, especially in early disease in children and there are very few studies in NCFB.12 As a Seminars in Respiratory and Critical Care Medicine

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consequence, the literature is based on airway tissue studies obtained either at postmortem or at the time of lung transplant, which limits the commentary on airway pathology to only very severe disease.13,14 The similarities between CF and NCFB have led to investigation of CFTR mutations in individuals with NCFB, based on the hypothesis that the presence of CFTR mutations may modulate NCFB disease severity or that some cases of NCFB represent a “forme fruste” of CF. Evidence of an increase in CFTR mutations in patients with NCFB has been reported in some, but not all, studies.15–21

Microbiology in CF Bronchiectasis and NonCF Bronchiectasis Articles “Fungi in CF and non-CF Bronchiectasis,” Non-tuberculous Mycobacteria in CF and non-CF Bronchiectasis,” and “The Microbiome and Emerging Pathogens in CF and non-CF Bronchiectasis” of this issue have provided in-depth overviews of the microbiology of CF and NCFB, but in this overview we have summarized this in the context of inhaled antibiotics and tried to highlight why it may be important to consider the “whole” microbiome when selecting the most appropriate antibiotic in an individual patient. Thus, we present the argument that detailed understanding of bacterial communities and how they may interact with one another and the host immune system in the lung will lead to better and more tailored therapy for the patient with bronchiectasis. In CF, based on routine microbiological culture results, the dominant pathogens early in life are Haemophilus influenzae (H. influenzae) and Staphylococcus aureus (S. aureus). While Pseudomonas aeruginosa (P. aeruginosa) infection is common in young children with CF, the institution of aggressive antibiotic programs by pediatric teams in recent years has been remarkably successful in eradicating it in the medium term, although with age chronic P. aeruginosa infection becomes increasingly more common (50–80% of adults in most cohorts).22–24 This change in the microbial landscape in adolescents and young adults will require clinicians to reconsider inhaled antibiotic-suppressive regimens in CF in the future. However, to date there have been few studies conducted in this emerging CF cohort to help guide prescribing practice in this situation, but this is where molecular characterization of the lung microbiome may be very informative.25 Other pathogens that increase in prevalence with age in CF include MRSA, Burkholderia cepacia (B. cepacia) complex, Stenotrophomonas maltophilia (S. maltophilia), Achromobacter xylosoxidans (A. xylosoxidans), Aspergillus species, and nontuberculous mycobacteria (NTM), but indications for the use of inhaled antibiotics targeting these microbial pathogens are uncertain, except in the setting of NTM where amikacin has been used as part of eradication regimens.22–24 In NCFB, several cohort studies have described the microbiological characteristics of patients based on routine microbiological culture methods. The most common pathogens in children with NCFB are nontypeable H. influenzae (NTHi), Streptococcus pneumoniae (S. pneumoniae), and Moraxella catarrhalis (M. catarrhalis).26,27 In adults, P. aeruginosa and


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should be employed in CF and NCFB remains unknown.47 In summary, the ability of molecular methods to accurately characterize the whole lung microbiome has driven exciting new insights in CF and NCFB. The challenge we now face is how to use this information in prospective studies of tailored inhaled antibiotic therapy across the spectrum of age and disease severity to improve patient outcomes.

Evolution of the Lung Microbiome in Cystic Fibrosis and Non-CF Bronchiectasis Over Time Changes in community composition and bacterial metabolic and phenotypic behavior over the lifetime of a patient are additional factors that need to be considered when prescribing inhaled antibiotic therapy in CF and NCFB. The “core” lung microbiome in healthy children was recently shown to be the same as in children with protracted bronchitis, NCFB, and CF, but this differed from the core microbiome in adults with NCFB and CF.48 These observations suggest that the lung microbiome in disease states may diverge from the normal core microbiome over time. Whether this divergence occurs as a consequence of lung disease progression or whether it is an effect of long-term antibiotic pressure is unknown and requires further study. However, longitudinal alterations in the lung microbiome over time should be considered when inhaled antibiotics are being used as long-term therapies, especially when there appears to be a reduction in clinical effectiveness over time.

Phenotypic Behavior of Bacteria in Cystic Fibrosis and Non-CF Bronchiectasis Data are emerging on bacterial survival strategies in CF, but less is known about what occurs in NCFB. However, increased understanding of bacterial behavior in the actual disease setting is required if antibiotic choices are to be optimized and new therapeutics developed. The majority of research to date has focused on P. aeruginosa behaviors in CF, particularly its propensity to grow in biofilm-like macrocolonies and its capacity to rapidly develop resistance to anti-pseudomonal antibiotics through multiple mechanisms including chromosomal mutations and by acquired resistance mechanisms.49,50 There are fewer data on P. aeruginosa behavior in NCFB and very little information on the behavior of other pathogens often present, in the airway of patients with CF or NCFB. For example, H. influenza and S. pneumoniae also have the capacity to form biofilms, which will serve to reduce the efficacy of inhaled antibiotics in vivo.51,52

The Lung Microenvironment The microenvironment of the airway may impact on the efficacy of inhaled antibiotics in CF and NCFB. For instance, the pH of the airway in CF and NCFB is reduced compared with that in healthy controls, which has been attributed to neutrophilic inflammation in both diseases, although this may be exacerbated in CF by a disturbance in the normal CFTRmediated flux of ions, including bicarbonate in mucous Seminars in Respiratory and Critical Care Medicine

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NTHi predominate, although other bacteria are also relatively common including S. aureus, S. pneumoniae, and M. catarrhalis and prevalence rates of the individual bacterial species vary considerably between studies.17,19,28–30 As examples of this variability in NCFB, P. aeruginosa rates ranged from 7 to 21% and normal respiratory flora from 15 to 35% of the patients studied. Details of coinfection (including fungi and mycobacteria) have been given limited attention in the literature. The advent of nonculture molecular methods based on pyrosequencing of 16S ribosomal DNA (rDNA) in sputum and bronchial lavage samples has revealed the presence of multiple bacterial organisms in both CF and NCFB that are not identified by routine culture methods.31,32 Emerging data from lung microbiome studies in CF have generated speculation about whether current treatment strategies need to be revised and whether other pathogens, particularly anaerobes, should be targeted with antibiotic therapy.32 In NCFB, there are fewer microbiome studies than in CF, but as information increases there is likely to be a similar degree of uncertainty over how best to treat the polymicrobial infection present.33 At present, the majority of inhaled antibiotic treatments in CF and NCFB target P. aeruginosa. There is clear logic to this strategy, as there are good data to show that chronic P. aeruginosa infection predicts for disease progression, poorer quality of life, and increased mortality in CF and NCFB.34–38 Prospective studies have shown that inhaled antibiotics reduce P. aeruginosa bacterial load overall accompanied by clinical improvements and reduced pulmonary exacerbation rates.39,40 However, examination of bacterial communities based on pyrosequencing of the 16S rRNA gene has shown that P. aeruginosa may not always be the “dominant” pathogen in CF or NCFB.31,41 Furthermore, in CF, recent studies have demonstrated that the lung microbiome and proportionate contribution of P. aeruginosa to the overall bacterial community changes very little with aggressive intravenous antibiotic therapy.32,42,43 These studies have been mainly conducted in adults with severe CF, but they do raise the question of whether long-term inhaled antibiotics will reduce the burden of P. aeruginosa infection in advanced CF. Finally, there are very few data to guide the use of inhaled antibiotics in CF or NCFB when P. aeruginosa is either absent or its contribution to the microbiome is relatively small. The proportion of CF patients without P. aeruginosa infection (on routine culture) transitioning to adult care is rapidly increasing and a substantial proportion of patients with NCFB do not have evidence for P. aeruginosa infection. In NCFB, studies are beginning to stratify patients based on 16S rRNA community profiles into groups depending on the dominant taxa present—that is, Pseudomonadaceae, Streptococcaceae, or Pasteurellaceae.33 The biological relevance of this sort of classification remains uncertain, but may well impact on the efficacy of different antibiotics. Finally, the potential importance of obligate anaerobes has been recently highlighted with culture-independent molecular methods revealing that anaerobic pathogens contribute significantly to the core microbiome in CF,44–46 but with less information available in NCFB. The relevance of anaerobes to disease pathogenesis in both CF and NCFB has not yet been elucidated and, thus, whether antibiotics that cover anaerobes

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glands.53,54 A reduced airway pH has implications for the efficacy of antibiotics such as the aminoglycosides, which are less effective in acidic environments.55 A direct comparison of airway pH in CFB and NCFB has not been undertaken, but assessment of the degree of acidification of the airway may require consideration in future inhaled antibiotic trials, as a low pH may contribute to apparent treatment failures. The microenvironment of the airway may also differ in terms of the partial pressures of oxygen present. Oxygen levels in the airways of the diseased CF lung may be low and conditions in a mucous occluded airway may be frankly anaerobic.56 Low oxygen levels also serve to reduce antibiotic efficacy, particularly in the depth of biofilms where resident bacterial communities adopt a metabolically quiescent existence.57,58 Airway microenvironmental oxygen levels have not been measured in NCFB, although it is probable that low oxygen conditions will be present in dilated, inflamed, and mucous filled airways just as they are in CF.56

Inhaled Antibiotics in Cystic Fibrosis Inhaled antibiotics specifically targeted to P. aeruginosa have broadly several treatment objectives including eradication of early infection, management of chronic P. aeruginosa infection, and the use of nebulized antibiotics as therapeutic modality of pulmonary exacerbations.59 To date, most studies of inhaled antibiotics have addressed their role in patients with P. aeruginosa infection. Several approaches to evaluate the role of inhaled antibiotics in patients with other bacterial pathogens have recently been undertaken, in an attempt to eradicate MRSA and to treat chronic B. cepacia complex infection.60,61

Inhaled Antibiotics for Chronic Infection in CF Meta-Analysis The role of nebulized anti-pseudomonal antibiotics in CF has been analyzed in a Cochrane Review by Ryan and colleagues.40 The review identified 19 trials that included 1,724 participants, and in 17 trials an inhaled antibiotic (tobramycin in 8) with placebo or usual treatment. The duration of the trials varied from 1 to 32 months. The key findings were (1) higher lung function (percentage of forced expiratory volume in 1 second [FEV1%] predicted) and (2) reduced pulmonary exacerbations in the antibiotic-treated group. On the converse, antimicrobial resistance was higher in antibiotic-treated group compared with placebo. Cough, hemoptysis, altered voice, and tinnitus were more common in participants receiving tobramycin. One trial comparing tobramycin with colistin demonstrated lung function was increased in the patients receiving tobramycin only.40 In this article, we provide details of the clinical trials supporting the use of specific antibiotics that appear in therapeutic guidelines (►Tables 1 and 2).

Clinical Trials in Chronic Infection Tobramycin Tobramycin is an aminoglycoside which is bactericidal against most gram-negative bacteria, but notably not against Seminars in Respiratory and Critical Care Medicine

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B. cepacia complex or S. maltophilia. Several early trials of variable treatment durations (3 to >32 months) demonstrated positive impact on lung function but were limited by small sample sizes, often single-center studies, used low doses of antibiotic, and had potential flaws in trial design.71,75–78 A study of 22 CF patients receiving inhaled tobramycin three times a day for 12 weeks validated the safety profile and the efficacy in reduction of sputum bacterial density and reduction in cough and sputum production.79 Higher doses of tobramycin were thought to be required for Pseudomonas bactericidal effect. In a multicenter, double blind, placebocontrolled crossover trial,62 71 patients received 600 mg of preservative-free tobramycin sulfate dissolved in 30 mL half strength physiologic saline (adjusted to a pH of 6.86–7.05) or matched three times per day via ultrasonic nebulizer (Ultraneb 100/99; De Vilbiss, Somerset, PA). The study confirmed that short-term aerosol administration of high-dose tobramycin in patients with CF was effective and safe for treatment of P. aeruginosa. Subsequently, two large multicenter, double-blind, placebo-controlled trials in patients with CF published in a single article demonstrated longer-term tolerability, safety profile, and efficacy of tobramycin inhalation solution (TIS).63 A total of 520 patients with P. aeruginosa were recruited from 69 CF centers in the United States. Participants were randomized to receive either 300 mg of nebulized TIS or placebo twice daily for 4 weeks, followed by 4 weeks with no study drug, in three on–off cycles over a study duration of 24 weeks. The patients treated with nebulized TIS had 10% improvement in FEV1% predicted (p < 0.001), decreased in sputum P. aeruginosa load (p < 0.001), and a 26% reduction in risk of hospitalization (95% confidence interval, 2–43% [p ¼ 0.014]) at week 20. Notably, the improvement in lung function was most marked in the adolescent age group (14–17 years). An open-label extension of alternating cycles of TIS (28 days on and 28 days off) for 2 years confirmed lung function was maintained above the baseline and there was a 25 to 33% reduction days in the hospital compared with placebo group.64 Intravenous antibiotic therapy and oral quinolone therapy were reduced over study period. The effect of inhaled TIS solution was studied in an open-label, parallel-group, multicenter study randomizing 184 CF patients with mild lung disease to routine subject management (control group) or routine management plus alternate month TIS for 56 weeks.65 This study was prematurely terminated, as an interim safety review showed increased risk of respiratory hospitalization for control group subjects. Nebulized TIS was generally well tolerated. Significant renal toxicity and hearing loss have not been reported. Transient mild to moderate tinnitus and voice alteration were the only adverse events reported in a significantly greater percentage of the TIS group than in the placebo group. Most episodes of tinnitus were transient and mild or moderate in severity.63 A similar side effect profile in the open-label extension of the study has been reported with longer-term use.64 Bronchoconstriction and or bronchospasm have been reported following TIS,80 but the use of β-agonists may prevent decline in lung function.80,81


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520 CF (TIS 258 vs. placebo 262) 6 y—mean (SD) age: 20.7 (9.5) y FEV1: 50 (16)% predicted Exclusion criteria: B. cepacia, renal impairment, aminoglycoside hypersensitivity, and anti-pseudomonal antibiotic baseline and fewer days in the hospital Tobramycin MIC did not predict response And no increase in resistant pathogens Most AEs declined with increasing TIS exposure, though Increase incidence of tinnitus and voice alteration

Not applicable

Open label extension

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157 CF 6 y of age with known P. aeruginosa Mean age: 19 y FEV1: 95% predicted Exclusion criteria: monobactam hypersensitivity to antibiotics, inability to tolerate bronchodilators or previous enrolment in an AZLI trial

101 CF 6 y of age with chronic Burkholderia spp. infection Mean age: 26 y FEV1: 57% predicted Exclusion criteria: monobactam hypersensitivity to antibiotics, inability to tolerate

Wainwright et al70 Multicenter United States/Canada/Australia 40 sites 2011

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Tullis et al61 Multicenter United States/Canada 35 sites 2014

Double blind, parallel group RCT AZLI 75 mg (or placebo) tid administered continuously for 24 wk eFlow electronic nebulizer

Double blind, parallel group RCT Single 28-d AZLI 75 mg (or placebo) tid eFlow electronic nebulizer

Double blind, parallel group RCT 28 d of AZLI 75 mg (or placebo): bid or tid eFlow electronic nebulizer with PARI Innovative

Double-blind, parallel group RCT Pretreatment with TIS, then 28 d of AZLI 75 mg (or placebo): bid or tid eFlow (Altera) electronic nebulizer

Antibiotic

Chronic Burkholderia spp. (all)

P. aeruginosa (all)

P. aeruginosa (all)

P. aeruginosa (all)

Pathogen(s)

No treatment differences (AZLI vs. placebo) at week 24 for FEV1% predicted, number of respiratory exacerbations or hospitalizations

HRQoL as primary endpoint (resp. domain CFQ-R) and there was no significance difference between groups AZLI resulted in a greater reduction in mean log10 P. aeruginosa CFUs in sputum and greater increase in adjusted mean relative change in FEV1% predicted

AZLI improved endpoint: Mean CFQ-R respiratory score (9.7 points) FEV1 (10.3% predicted Sputum P. aeruginosa density compared with placebo

AZLI superior to placebo Delayed time to IV antipseudomonal antibiotics (AZLI 92, placebo 71 d) Improved respiratory symptoms (mean CFQ-R respiratory scores by 5.0 points) Improved pulmonary function (FEV1 improved by 6.3% Reduction in sputum P. aeruginosa density

Clinical impact

Incidence of the most common AEs were generally comparable between treatment arms, although wheezing and chills were reported for more AZLI-Rx A fourfold increase for the aztreonam MIC for

Incidence of AEs was similar for both treatment groups In AZLI Rx group, P. aeruginosa isolates MIC increased from baseline to day 14 ( 1 μg/mL to 4 μg/mL) which was maintained at days 28 and 42. These were unchanged in the placebo group during the study

Adverse events were consistent with symptoms of CF lung disease and comparable for AZLI and placebo Incidence of productive cough was less in AZLI group (AZLI 12.5% vs. placebo 25%) P. aeruginosa aztreonam susceptibility at baseline and end of study were similar

AEs for AZLI and placebo were comparable and consistent with underlying CF lung disease Susceptibility of P. aeruginosa to aztreonam at baseline and end of study were similar

Adverse effects

A 24-wk extension period of open-label AZLI treatment61 for all subjects (weeks 24–48); and a 4-week follow-up period (weeks 48–52): 84/100 continued in the open

Not applicable

Oermann68: open label extension study from RCTs67,69 of 71 sites and 4 countries) Patients received up to 9 courses (28-d on/28-d off) of AZLI 75 mg either bid or tid Mean adherence (92.0% bid group, 88.0% tid group) AZLI improved FEV1% predicted, CFQ-R scores and reduction in sputum P. aeruginosa density Hospitalization rates were low A dose response was observed; AZLI TID-Rx subjects had greater improvements Benefits waned in the 28-d off Rx but weight gain sustained over the 18 mo AEs were consistent with symptoms of CF lung disease and were similar between the two dosing arms There were no sustained decreases in P. aeruginosa susceptibility




164 CF 6 y of age with P. aeruginosa Mean age: 29 y FEV1: 54% predicted Exclusion criteria: recent antipseudomonal antibiotics, azithromycin, oral prednisolone (10 mg daily) or hypertonic saline; B. cepacia complex (previous 2 y); daily continuous oxygen supplementation or at night

211 CF 6 y of age with P. aeruginosa Mean age: 26 y FEV1: 55% predicted Exclusion criteria: oral corticosteroid use (prednisone 10 mg daily); Burkholderia cepacia complex in the previous 2 y; oxygen (daily continuous or night; monobactam hypersensitivity

Numbers, population, exacerbations

Retsch-Bogart et al 69 Multicenter International 53 sites 2009

McCoy et al67 Multicenter United States 56 sites 2008

Aztreonam

Author, site, year

Table 1 (Continued)

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Early studies did not report increased resistance to the nebulized antibiotics and no increased new infection with multiresistance organisms.63,72 Microbiology from the large randomized controlled trial (RCT) of TIS and showed no increase in the isolation of multiresistant pathogens (e.g., B. cepacia, S. maltophilia, or A. xylosoxidans). Isolation of Candida albicans and Aspergillus species did increase, although the significance of this finding is unclear.82 Tobramycin was associated with an increase in the percentage of patients having sputum P. aeruginosa with a tobramycin minimum inhibitory concentration (MIC) >16 mg/mL (from 13 to 25%), and the beneficial effect on lung function and other clinical trial endpoints appeared to be independent of these microbiologic variables. Sputum P. aeruginosa density decreased during each of the three on-drug periods, suggesting that “tobramycin resistance” associated with TIS did not affect the sputum P. aeruginosa density and clinical improvement even at the end of the third treatment cycle. In the longer-term analysis, a similar percentage of patients had improved FEV1 in patients with resistant strains of P. aeruginosa (MIC values ranging from 16 to 64 μg/mL) when compared with those patients with susceptible P. aeruginosa (MIC values of 8 μg/ mL).64 Given the daily burden of nebulized therapies in patients with CF and lower adherence reported to inhaled therapies, initiatives to reduce time for inhaled treatments have been welcomed. One such approach was the development of tobramycin inhalation powder (TIP). Two phase III trials were subsequently initiated comparing TIP with TIS; the first RCT was stopped prematurely after an interim analysis and final analysis were completed after a large number of exclusions, but the conclusion was that TIP was associated with greater improvements in lung function than TIS.66 The second study, using a noninferiority design over 24 weeks, confirmed TIP’s effectiveness.83

Aztreonam Lysine Aztreonam lysine for inhalation (AZLI) is a lyophilized formulation of the monobactam antibiotic, aztreonam with lysine as an excipient, and specifically designed for inhalation therapy. The intravenous aztreonam formulation contains arginine, which can lead to airway inflammation with repeated inhalation in patients with CF.84 AZLI is active against gram-negative aerobic organisms by inhibiting bacterial cell wall synthesis, demonstrates clinically significant synergy with aminoglycosides against P. aeruginosa, and is stable to most β-lactamases. In a phase I study, inhaled AZLI was well tolerated and sputum concentrations exceeded the MIC for P. aeruginosa.85 A phase II dose-ranging trial reported the optimal dose of 75 mg three-times daily and noted that higher doses were associated with increased adverse events, including more frequent and severe cough.86 Two RCTs which included 246 and 164 patients randomized participants to AZLI 75 mg three-times daily (or placebo).67,69 These studies showed increased time-to-next pulmonary exacerbation67 and greater improvement in the respiratory domain of the CF-specific health-related quality of life (HRQoL) tool (CFQ-R)69 as primary endpoints for the two studies, respectively. Seminars in Respiratory and Critical Care Medicine

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P. aeruginosa (all) Open label, parallel group Colistin 1 106 units or placebo (0.9% saline) bid for 90 d Raindrop Jet nebulizer 42 CF Chronic P. aeruginosa infection Mean age: 14 y FEV1: 75% predicted Prior to enrolment all patients received 2 wk of IV antibiotics Jensen et al71 Single center Denmark 1987

Colistin

bronchodilators or previous enrolment in an AZLI trial

Abbreviations: AE, adeverse events; AZLI, aztreonam lysine for inhalation; bid, twice a day; CF, cystic fibrosis; CFU, colony forming units; FEV, forced expiratory volume in 1 second; IV, intravenous; MIC, minimum inhibitory concentration; NCFB, non-CF bronchiectasis; RCT, randomized controlled trial; tid, three times a day; TIS, tobramycin inhalation solution.

Not applicable AEs: irritating cough (1) and taste disturbance (2) (both placebo) and burning sensation in the mouth (1) (colistin)

label extension and 76 subjects completed the second 24-wk study period Clinical efficacy no different during the second 24wk study period AE incidence were generally comparable to those observed during initial 24wk study period Burkholderia spp. in the AZLI, but not the placebo arm (week 24)

Pathogen(s) Author, site, year

Table 1 (Continued)


Antibiotic

Clinical impact

29 subjects completed trial (more in colistin group)

Open label extension Adverse effects



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Assael et al74 UK and United States Multicenter 91 site 2013

Open label, parallel group trial Three 28-d courses of AZLI 75 mg tid vs. tobramycin 300 mg bid; 28 offdays

Open label, parallel group trial Colobreathe dry powder for inhalation (CDPI) colistimethate sodium 1.6 106 IU, bid) vs. three 28-d cycles TIS (300 mg) bid Study duration—24 wk

P. aeruginosa (all)

P. aeruginosa (all)

P. aeruginosa (all)

Pathogen(s)

AZLI statistical superiority vs. TIS (FEV1% predicted) Mean relative changes in FEV1 after 1 course (AZLI: 8.35%; TIS: 0.55%;

CDPI is noninferior to TIS (FEV1% predicted). Similar for FVC and CFQ-R CDPI group rated device as ‘very easy or easy to use’ (91% vs. TIS 54%)

TIS mean increase in FEV1 of 6.7% and no change with colistin Both led to significant decrease in sputum P. aeruginosa density

Clinical impact

AEs: cough (AZLI: n ¼ 7/22; TIS: n ¼ 4/11) and productive cough (AZLI: n ¼ 4/22; TIS: n ¼ 5/11) 15 patients

AEs were similar in both groups Increased rates of cough (CDPI 75% vs. TIS 44%), throat irritation (CDPI 45.5% vs. TIS 28.0%), abnormal taste (CDPI 62.6% vs. TIS 27.5%), and hemoptysis (CDPI 10.7% vs. TIS 6.7%). Discontinuation rates higher with CDPI (32 vs. 21 patients) most due to AEs No increase in colistin-resistant isolates

Incidence of AEs was comparable between groups Pharyngitis was more common in the TIS group whereas cough in the colistin group Small increase in MIC in TIS Rx group and no change in the colistin Rx group

Adverse effects


273 CF 6 y with P. aeruginosa within last 3 mo and FEV1 4 µg/mL and approached 50% at the end of the trial


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Abbreviations: AE, adeverse events; AZLI, aztreonam lysine for inhalation; bid, twice a day; CF, cystic fibrosis; CFU, colony forming units; FEV, forced expiratory volume in 1 second; IV, intravenous; MIC, minimum inhibitory concentration; NCFB, non-CF bronchiectasis; RCT, randomized controlled trial; tid, three times a day; TIP, tobramycin inhalation powder; TIS, tobramycin inhalation solution.

Konstan et al66 International Multicenters 127 sites 2011

Tobramycin (TIS vs. TIP)

Author, site, year

Table 2 (Continued)

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Improvements in the AZLI groups of secondary endpoints (including changes in lung function and sputum P. aeruginosa density) were seen. Importantly, there was no increase in MIC of P. aeruginosa in these trials67,87 and no differences in the isolation of new pathogens.67 Increased rates of hemoptysis and voice alteration were noted in one study.67 In an 18month open-label extension trial, AZLI was well tolerated, safe, and remained effective, including the positive effects on FEV1 and HRQoL.68 In a short-term trial (28 days), AZLI did not demonstrate improved HRQoL or lung function in patients with mild lung disease.70

Colistimethate Sodium Colistimethate sodium is a polymyxin antibiotic which exerts its bactericidal effect by increasing cell membrane permeability for gram-negative bacteria. Inhaled colistimethate (colistin) has been used for many years in the treatment of P. aeruginosa infection. In Europe, nebulized colistin has been used in patients with chronic P. aeruginosa infection for many years either continuously or alternative month therapy— commonly alternating with inhaled tobramycin (i.e., 28 days colistin, then 28 days tobramycin).59 Importantly, despite very long duration of administration, rates of P. aeruginosa resistance to colistin have remained very low.73 A single-center RCT enrolled 40 participants with CF and chronic P. aeruginosa infection to compare nebulized colistin (1 million units nebulized twice daily) and placebo (isotonic saline solution) and in a 3-month study.71 Patients were recruited on completion of a treatment course of intravenous antibiotics for an exacerbation. Significantly, more patients who received colistin completed the study, had a greater improvement in clinical symptom score, and maintained pulmonary function. A second RCT was performed over a 6month period, although limited information is available about the study as it was published only in abstract form.88 As with tobramycin, a dry powder preparation of colistin has been recently developed in a phase III study comparing colistin (125 mg bid) with TIS (300 mg bid) over 24 weeks with threecycle on-and-off drug.73 Based on a noninferiority design, the endpoint of mean difference in FEV1 was achieved. Subsequently, the European Medicines Agency (EMA) has approved its use as a treatment for chronic P. aeruginosa infection.

Comparative Antibiotic Trials An open-label, comparative trial between TIS (300 mg bid) and colistin (1 106 units bid) showed a significant increase in FEV1 for the TIS group (6.7% predicted), but no change in the colistin-treated group (►Table 2).72 This occurred despite an increase in the proportion of participants with resistant P. aeruginosa strains (TIS group) and no change in the colistintreated group. One of the significant limitations of this trial was that patients had been prescribed colistin before entry into the study, yet patients were naive to TIS, potentially favoring a greater improvement in lung function. A second limitation was that the study was unblinded due to differences in drug administration, drug appearance, and its taste, potentially leading to bias in favor of TIS, a new agent to participants. Seminars in Respiratory and Critical Care Medicine

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In an open-label, randomized, parallel-group, noninferiority trial, AZLI and TIS were compared in patients with CF and P. aeruginosa (n ¼ 273). Patients were randomized to three 28-day courses of either AZLI or TIS, followed by 28 days off therapy. The trial design was complex and had coprimary endpoints: (1) noninferiority of AZLI for relative change from baseline in FEV1% predicted at day 28 and (2) superiority of AZLI for actual change from baseline in FEV1% predicted compared with TNS across the treatment cycles. Statistical superiority in lung function and fewer respiratory hospitalizations (p ¼ 0.044) and respiratory events requiring additional anti-pseudomonal antibiotics (p ¼ 0.004) was seen in the AZLI-treated group. Notably, similar rates of adverse events have been reported with AZLI and tobramycin.74 In an article (titled Aztreonam for inhalation solution, challenges to drug approval and integration into CF care), Goss and Bell highlighted many of the challenges of trial design of comparator studies including differing requirements for trial endpoints by the Food and Drug Administration (FDA) and EMA.89

Consensus and Guideline Recommendations The use of chronic suppressive therapy with inhaled antibiotics is currently the standard of care for CF patients with chronic P. aeruginosa. Based on the meta-analysis and clinical trials outlined earlier, several consensus or guidelines have been developed, which are broadly similar, and these are summarized here.59,90,91 Nebulized tobramycin (TIS) is the first nebulized antibiotic approved for CF by the FDA and EMA in 1997. The CF Foundation and European Cystic Fibrosis Society (ECFS) guidelines recommend the chronic use of inhaled tobramycin to improve lung function and reduce exacerbations for patients with CF who are 6 years of age and who have moderate to severe lung disease with chronic P. aeruginosa in airway cultures.59,90,91 The CF Foundation guidelines recommend the chronic use of inhaled tobramycin for patients 6 years of age who are asymptomatic or have mild lung disease to reduce exacerbations.92 Dry powder formulation of tobramycin (TIP, TOBI Podhaler, Novartis Corporation, New York, NY) has equivalent efficacy as nebulizer solution and is available in many countries and is a suitable alternative. Inhaled AZLI is recommended as an alternative by both European and U.S. guidelines.59,90,91 The role of colistin (2 106 units twice daily) is less well supported in published guidelines; however, it continues to be widely used in Europe, Australia, and New Zealand and is now also available as a dry powder preparation.

Inhaled Antibiotics for Eradication of P. aeruginosa Eradication of early P. aeruginosa infection is a standard of care in many CF centers internationally.59,90,91 The Danish approach was the first to successfully eradicate P. aeruginosa infection using a combination of 3 months of oral ciprofloxacin and nebulized colistin.92 In a recent Cochrane review, it was shown that nebulized antibiotics were better than no treatment for early infection with P. aeruginosa and that eradication can be long term and up to 2 years. Currently, it is unclear if eradication leads to improved quality of life, impacts on mortality, or has adverse consequences including


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Inhaled Antibiotics for Treatment of Pulmonary Exacerbations Inhaled antibiotics can potentially be used in mild exacerbations (often in combination with oral ciprofloxacin) to treat patients who are not sufficiently unwell enough to warrant parenteral therapy as a trial. While this is common clinical practice, studies to support the effectiveness and safety of this approach are lacking. Inhaled antibiotics may also be used as an alternative to intravenous antibiotics for the treatment of pulmonary exacerbations in combination with a parenteral antibiotic (e.g., nebulized tobramycin in substitution for intravenous tobramycin). Similarly, there is limited evidence to support this practice. In a recent Cochrane review, four studies were identified.95 However, the finding of this review included that the studies were underpowered and were unable to demonstrate that one approach was superior. This area requires further study, especially given the reports of renal and ototoxicity in patients with CF and the increasing lifetime burden of systemic aminoglycosides which is likely to continue to grow with increasing longevity and more aggressive approaches to treatment of exacerbations.

Inhaled Antibiotics in the Pipeline Liposomal Amikacin (Arikace) Arikace is a sustained-release liposomal preparation of amikacin suitable for nebulization, which has potent anti-pseudomonal (among other antibacterial and antimycobacterial) effects and prolonged lung deposition. On nebulization, Arikace liposomes penetrate CF sputum where they are lysed and results in prolonged lung half-life (several hours) relative to liposomefree antibiotics.96 It is effective in reducing P. aeruginosa density in animal models of lung infection and in preclinical model pharmacokinetics support once-daily dosing. A phase II RCT randomized to once-daily Arikace (70, 140, 280, or 560 mg) or placebo for 28 days in 105 patients with CF. Arikace was well tolerated, safe, and had biological activity and efficacy in patients with CF with P. aeruginosa infection.97 There were no concerning adverse events with Arikace. The relative change in FEV1 was higher in the 560-mg-dose group at day 28 (p ¼ 0.033) and at day 56 (28 days posttreatment, p ¼ 0.003) when compared with placebo. In parallel, sputum P. aeruginosa density decreased >1 log in the 560-mg group compared with placebo. An open-label extension (560 mg Arikace) for 28 days followed by 56 days off therapy over six cycles confirmed durable improvements in lung function and sputum P. aeruginosa density. A phase III clinical trial program is underway and one of these is completed though yet to be

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formally reported. However, in a recent review, noninferiority for lung function was demonstrated for nebulized Arikace (560 mg daily) compared with tobramycin (300 mg bid) and the therapy was well tolerated.60

Inhaled Quinolones (Levofloxacin and Ciprofloxacin) Levofloxacin is a fluoroquinolone which has potent activity against P. aeruginosa. MP 376 is a formulation suitable for inhalation, with high concentrations of levofloxacin packaged with magnesium chloride to enable rapid absorption. A phase I initial study demonstrated that aerosolized MP-376 was well tolerated and produced levofloxacin concentrations in sputum sufficient for bacterial killing.98 A further multicenter doseranging study showed that 240 mg twice daily led to a dosedependent increase (8.7%) in FEV1 compared with placebo (p ¼ 0.003), reduced sputum P. aeruginosa density, and decreased need for other anti-pseudomonal antibiotics.99 The major adverse event was mild–moderate dysgeusia (unpleasant taste), although this did not necessitate withdrawal from the study. Two phase III trials have recently been completed (NCT01180634, NCT01270347) and the results will hopefully open more nebulized treatment options in the future.60 Two preparations of ciprofloxacin are currently being trialed in CF, including liposomal preparation of ciprofloxacin in combination with free ciprofloxacin (Aradigm Corporation, Hayward, CA) and a dry powder preparation of ciprofloxacin (Bayer AG, Leverkusen, Germany).

Fosfomycin/Tobramycin Fosfomycin in combination with tobramycin (4:1 ratio) for inhalation has been developed for use in patients with chronic P. aeruginosa infection. Fosfomycin is a phosphoric acid antibiotic which inhibits bacterial cell wall synthesis and is active against gram-negative, gram-positive, and anaerobic bacteria, including MRSA. A randomized placebo-controlled, multicenter study of 119 patients where participants were enrolled after a 28-day course of AZLI showed a significant improvement in FEV1 (7.5% improvement, p < 0.001) and reduction in P. aeruginosa density (p ¼ 0.02) in the 80/20 mg twice-a-day dosing group.100 There were fewer side effects in 80/20 mg group as compared with higher dosing group which may have contributed to its greater apparent efficacy.

Vancomycin Chronic MRSA infection has increased in prevalence over the past 20 years in patients with CF and has been associated with adverse clinical outcomes. Treatments are limited and a phase IIa dose-ranging trial has recently completed recruitment for a RCT to examine safety and efficacy of vancomycin inhalation powder.60 Results are anticipated in early 2015.

Inhaled Antibiotics for Non-CF Bronchiectasis As with CF, the principle in using inhaled antibiotics is to deliver high concentrations of antibiotics directly to the site of infection (e.g., airway) and limit the potential for systemic toxicity and adverse effects. The goal of inhaled antibiotic Seminars in Respiratory and Critical Care Medicine

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the establishment of other bacterial infections or increases antibiotic resistance.93 Similar results were reported in multiple clinical trials with high rates of eradication (in some studies exceeding 90%).93,94 None of the protocols reported have demonstrated clear superiority and it remains to be established if combined treatment approaches (inhaled and oral therapies, initial intravenous antibiotics followed by inhaled antibiotics) are superior to inhaled-only approaches (e.g., 28 days of nebulized TIS).93

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therapy is to reduce bacterial load and its associated airway inflammation when eradication of lower respiratory pathogens is not practical. Importantly, all studies to date have evaluated the role of inhaled antibiotics in adults with NCFB and their role in children is therefore less certain.39 Most of the RCTs of inhaled antibiotics in NCFB have included patients with P. aeruginosa infection (►Table 3).101 However, there were several notable exceptions including the studies of aztreonam (included gram-negative infections), gentamicin (included patients without Pseudomonas), and the study of liposomal amikacin (Insmed, Inc. TR02-107 trial report. Available from: www.insmed.com/pdf/Pub9%209_13_09. pdf) (included patients without Pseudomonas).

Inhaled Antibiotics for Chronic Infection in NCFB Meta-Analysis A meta-analysis of randomized trials to evaluate the efficacy and safety of inhaled antibiotics in patients with stable NCFB has been recently published.39 This meta-analysis included 12 studies involving 1,264 patients with NCFB until March 2014 (including 5 unpublished studies). Nine studies were randomized, double-blind, placebo-controlled trials and nine were multicenter studies. The key finding of this analysis was inhaled antibiotics were more effective than placebo (or symptom-based therapy) in reducing sputum bacterial load, eradicating the bacteria from sputum, and reducing the risk of acute pulmonary exacerbations. Inhaled antibiotics reduced the risk of having at least one acute exacerbation by 28%. The meta-analysis estimated the number needed to treat was 5 to prevent one additional exacerbation. There was no change in unscheduled hospitalization. Inhaled antibiotics were associated with a small, but statistically significant, reduction in FEV1% predicted. Importantly, only six studies involved interventions of 6 months or more and the remaining studies were for 1 month. All but one study involved nebulized medication, several using novel carriers of delivery (liposomal preparations) and a range of nebulizer devices from standard jet nebulizers to rapid delivery nebulizers. Nine trials reported health-related quality-of-life scores. Five trials used the St George’s Respiratory Questionnaire (SGRQ), with a higher score indicating a poorer HRQoL. One trial used both the SGRQ and Leicester Cough Questionnaire (LCQ), a HRQoL measure of chronic cough validated for use in NCFB. Two trials used a new, disease-specific tool, the Quality of Life-Bronchiectasis (QoL-B). The data from five trials with a total of 407 patients that used SGRQ were suitable for the meta-analysis, showing no statistically significant difference in the change between the inhaled antibiotic and control groups. Bronchospasm was the most common adverse event, occurring in 10% of patients treated with inhaled antibiotics compared with 2.3% in the control group. Notably, patients treated with inhaled aminoglycosides were almost five times more likely to have bronchospasm than those treated with placebo with an estimated number needed to harm of seven. In contrast, inhaled ciprofloxacin and colistin had similar rates of bronchospasm between groups. Both the inhaled Seminars in Respiratory and Critical Care Medicine

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antibiotic and control groups had similar rates of study withdrawal, suggesting that adverse events were generally tolerable. The emergence of bacterial resistance is a major concern for prolonged use of antibiotic therapy. In 445 patients from seven trials, the incidence of emergence of bacterial resistance was similar (7.8%—inhaled antibiotic group, 3.5%—control group). This difference was not statistically significant.

Clinical Trials in Chronic Infection Aminoglycosides (Tobramycin, Gentamicin, Amikacin) Inhaled antibiotics are well established in patients with CF and frequently utilized to attempt to eradicate P. aeruginosa and for suppressive therapy in chronic infection, yet there role is much less well understood in NCFB. A decade ago, only two RCTs have been performed examining the role of tobramycin in adults with NCFB.39,104,110 In recent years, several antibiotic agents have been studied. While several studies have demonstrated reduced sputum bacterial loads, the clinical impact has been variable. Inhaled TIS (300 mg bid) administered for 6 months led to reduced bacterial density in sputum and a significant reduction in exacerbations requiring hospitalization (by 80%). Despite such changes, lung function and quality of life were not significantly improved and many patients were unable to tolerate the therapy.39,103,110 In a second study, Drobnic and colleagues studied 60 patients (30 tobramycin, 30 placebo) using a crossover design over 6 months and demonstrated the mean ( SD) number of days and numbers of hospitalization episodes during TIS administration (0.15 0.37 and 2.05 5.03) were lower than those during placebo administration (0.75 1.16 and 12.65 21.8) (p < 0.05).104 A decrease in Pseudomonas density in sputum was associated with TIS administration (p ¼ 0.038). Trials of long-term inhaled antibiotics provide conflicting results for a clinical benefit, with the best evidence being provided for benefit by an open-label RCT on inhaled gentamicin.105 A 12-month course of gentamicin (80 mg bid) resulted in reductions in bacterial density in sputum. In parallel, numbers of exacerbations were reduced, eradication of many non-Pseudomonas bacterial species and increased time to first exacerbation. While exercise capacity increased and HRQoL improved, again there was no impact on lung function and 20% of patients reported symptoms consistent with bronchospasm. An early phase II study was performed examining two doses of liposomal amikacin (280 and 560 mg nebulized once daily for 28 days). This study (unpublished data) demonstrated a modest reduction in Pseudomonas sputum loads.39

Aztreonam Two parallel inhaled aztreonam (AZLI) RCTs have been recently published.108 Interestingly, the primary endpoint for these studies was a patient-reported outcomes, Quality of LifeBronchiectasis Respiratory Symptoms scores (QOL-B).109 These short-term trials randomized a total of 540 patients to two 4-week courses of AZLI 75 mg or placebo (three-times


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144 adults Recent exacerbation requiring antibiotics

Haworth et al108 UK, Russia, Ukraine 35 sites 2014

Colistin (1 megaunit bid): INeb (n ¼ 73) 6 mo- or until first exacerbation Placebo (n ¼ 71)

Ciprofloxacin (free (60 mg) and liposomal (150 mg) once daily): jet nebulizer 24 wk (3 cycles of 28 d on/ 28 d off Rx) Placebo (n ¼ 64)

Ciprofloxacin (32.5 mg bid): dry powder inhaler (n ¼ 60) 28 d (and 56 d follow-up) Placebo (n ¼ 64)

Gentamicin solution (80 mg bid): jet nebulizer (n ¼ 32) 12 mo (and 3 mo follow-up) Placebo (n ¼ 33)

Tobramycin (300 mg bid): jet nebulizer (n ¼ 30) 6 mo crossover design (1 mo washout)

Tobramycin (300 mg bid): jet nebulizer (n ¼ 37) 28 d (with 14 d follow-up) Placebo (n ¼ 37)

Antibiotic

P. aeruginosa (all)

P. aeruginosa (all)

H. influenza (24%) P. aeruginosa (54%) S. aureus (20%) S. pneumonia (7%) M. catarrhalis (6%)

H. influenza (46%) P. aeruginosa (42%) S. aureus (5%) S. pneumonia (2%)

P. aeruginosa (all)

P. aeruginosa (all)

Pathogen(s)

Reduced sputum P. aeruginosa loads at 4 and 12 wk SGRQ improved at 26 wk

Lower use of antibiotics for exacerbations (40 vs. 77%) P. aeruginosa not cultured in 60 vs. 14% Reduced sputum P. aeruginosa loads (at 28 d, less effect by 168 d)

Reduced sputum P. aeruginosa loads Increased pathogen eradication (35 vs. 8%) at end of Rx

Fewer exacerbations (median 0 vs. 1.5) Median time to first exacerbation (120 d vs. 62 d) Improved cough scores and less purulence Reduced sputum P. aeruginosa loads Increased eradication rates (P. aeruginosa 31%, other pathogens 93%)

During tobramycin arm (reduced episode numbers (0.15 vs. 0.75) and days (2.1 vs. 12.7). Decreased sputum P. aeruginosa.

Reduced sputum P. aeruginosa at 4 wk and 35% eradicated Placebo: no change

Clinical impact

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Wheeze leading to withdrawal in colistin group (7 vs. 1.5%)

Lower respiratory events in ciprofloxacin arm Higher rates of dysgeusia (20 vs. 0%) Nausea (20 vs. 0%)

No difference in adverse events

22% bronchospasm (2 withdrew) No gentamicin resistance reported Benefits lost by 3 mo of cessation

10% withdrew due to bronchospasm 4 of 5 deaths during the trial were on the tobramycin arm

Dyspnea (32 vs. 8%) Chest pain (19 vs. 0%) Wheezing (16 vs. 0%) Exacerbations requiring hospitalization (14 vs. 3%) 26% fourfold increase in MIC

Adverse effects

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42 adults Exacerbation 2 per year

65 adults Exacerbations 2 per year

Murray et al105 UK Single center 2011

Serisier et al107 Australia and New Zealand 11 sites 2013

30 adults (20 completed) Recent exacerbation requiring antibiotics

Drobnic et al104 Spain Single center 2005

124 adults Exacerbation 2 per year or 1 hospitalization

74 Adults Exacerbations: not recorded in entry criteria

Barker et al103 United States Single center 2000

Wilson et al106 UK, Europe, Australia, USA 35 sites 2013


Author, site, year

Table 3 Randomized controlled trials of non–cystic fibrosis bronchiectasisa

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Liposomal Amikacin (280 mg or 560 mg once daily): eFlow nebulizer (n ¼ 44) 28 d (with 28 d follow-up) Placebo (n ¼ 20)

Two identical protocols (AIRBX1 and AIR-BX2) Aztreonam 75 mg tid): eFlow nebulizer AIR-BX1 (n ¼ 134) AIR-Bx2 (n ¼ 136) 2 cycles of 28 d (each cycle followed by 28 d off Rx), then open-label extension for a further 28 d

Antibiotic

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P. aeruginosa (all)

P. aeruginosa (81%) Achromobacter, Burkholderia, Citrobacter, Enterobacter, Escherichia, Klebsiella, Moraxella, Proteus, Serratia, Stenotrophomonas. Presence of H. influenzae alone did not meet study inclusion criteria

Pathogen(s)

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Significant reduction in P. aeruginosa density (560 mg vs. placebo) Fewer pulmonary exacerbations (4.7%) vs. those receiving placebo (10.5%) No patients in the LA inhaled group required anti-pseudomonal rescue treatment while 3 patients in the placebo group

The difference between AZLI and placebo for adjusted mean QOL-B were similar at 4 wk (0.8 [95% CI – 3.1 to 4.7], p ¼ 0.68) in AIRBX1, but was significant (4.6 [1.1–8.2], p ¼ 0.011) in AIR-BX2. The 4.6 point difference in QOL-B after 4 wk was not clinically significant. Decreases in sputum bacterial loads were larger for AZLI-treated patients than for placebo-treated patients at weeks 4 and 12 Culture-negative samples were greater in the AZLI treatment groups compared with placebo for Pseudomonas, Klebsiella, Escherichia, Enterobacter, at weeks 4 and 16

Clinical impact

Rx-related adverse events were consistent with underlying NCFB No evidence of renal or ototoxicity Slightly higher frequency of dry cough (short duration and self-limiting) post nebulizer (560 mg dose) One patient discontinued due to dysphonia and cough

Rx-related adverse events were more common in the AZLI group (most common were dyspnea, cough, and increased sputum) Discontinuations from adverse events were more common in the AZLI group

Adverse effects



Abbreviations: AZLI, aztreonam lysine for inhalation; bid, twice a day; FEV, forced expiratory volume in 1 second; LA, liposomal amikacin; MIC, minimum inhibitory concentration; NCFB, non–cystic fibrosis bronchiectasis; SGRQ, St George’s Respiratory Questionnaire; tid, three times a day. a Adapted with permission from Grimwood et al.101

64 adults FEV1 50% Chronic P. aeruginosa infection HRCT confirmed bronchiectasis in >2 segments History of at least 1 exacerbation, and 80%) had increased time to first exacerbation (168 days active therapy and 103 days placebo). P. aeruginosa density was reduced after 4 (p ¼ 0.001) and 12 weeks (p ¼ 0.008). The SGRQ HRQoL total score was improved after 26 weeks in the colistin group compared with placebo group, respectively. There were no concerns of increased adverse events in the colistin patients.

Ciprofloxacin Two formulations of inhaled ciprofloxacin have recently been developed for study in airway infection, as highlighted previously. In an early phase II study (ORBIT 1), two doses of ciprofloxacin were administered (100 and 200 mg once daily for 28 days) and demonstrated reduction in Pseudomonas density of sputum.39 Two phase II studies have recently been published and have led to the initiation of phase III trials of both products in patients with NCFB.106,107 Nebulized liposomal and free ciprofloxacin decreased sputum bacterial density in a 6-month trial (three alterative month dosing periods) and was well tolerated and reduced exacerbation rates, though again there was no change in lung function, nor exercise capacity or HRQoL in this study.107 Inhaled dry powder ciprofloxacin in a RCT study (of 60 patients active therapy and 64 patients on placebo who were culture positive for predefined potential respiratory pathogens—including P. aeruginosa and H. influenzae) was randomized to ciprofloxacin dry powder inhaler (DPI) 32.5 mg or placebo twice daily for 28 days (with 56 days of follow-up).106 Ciprofloxacin DPI resulted in a significant reduction in total sputum bacterial load compared with placebo. In the ciprofloxacin DPI group, 35% reported pathogen eradication at the end of treatment versus 8% in the placebo group. Ciprofloxacin DPI for 28 days was well tolerated and no abnormal safety results were reported and rates of bronchospasm were low.106

Consensus and Guideline Recommendations There are several treatment guidelines for the care of patients with NCFB, including those published by the British Thoracic Society (BTS) (2010) and the Thoracic Society of Australia and New Zealand (TSANZ) (2014) and guidelines for the management of adult lower respiratory tract infections published by the European Respiratory Society (ERS) (2011).21,111,112 The BTS and ERS guidelines were published several years ago and will not have considered many of the very recent studies published since 2011. The ERS guidelines do not recommend

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the use of nebulized antibiotics (tobramycin) in NCFB as prophylactic antibiotics.112 The BTS, however, do recommend patients to be considered for long-term nebulized antibiotics when having three or more exacerbations per year which require antibiotics or in patients with fewer exacerbations which are severe in nature (i.e., significant morbidity).21 In such patients, long-term nebulized antibiotics should be considered if individual patients have evidence of chronic P. aeruginosa infection and the choice of antibiotic should be guided by the antibiotic-sensitivity results of airway pathogens. These guidelines also highlighted the need for further studies particularly to assess the optimal antibiotic (including doses). Finally, the recently updated TSANZ guidelines recommended that long-term inhaled antibiotics (e.g., aminoglycosides, colistin) should not be prescribed routinely, though a therapeutic trial could be considered in children and adults with frequent exacerbations and or P. aeruginosa infection.111

Inhaled Antibiotics for Eradication There are no RCTs examining the role of inhaled antibiotics in eradication of new bacteria from the airways in patients with NCFB available to guide clinical practice. Notwithstanding, several inhaled antibiotic trials in NCFB have shown eradication of bacteria during the inhaled antibiotic intervention period (►Table 3).39

Inhaled Antibiotics for Treatment of Pulmonary Exacerbations While an attractive option for mild exacerbations and potentially in combination with oral antibiotics, there are no RCTs that have evaluated the role of inhaled antibiotics in the treatment of exacerbations of NCFB. In an uncontrolled study of 53 adults with NCFB and Pseudomonas infection undergoing an exacerbation, inhaled tobramycin in combination with ciprofloxacin was compared with ciprofloxacin alone.113 While a greater impact on bacterial load in the sputum was seen, there was no difference in clinical impact. As described previously, wheeze was common in the tobramycin group (50%) compared with the nontobramycin group (15%). Until further evidence is available, inhaled therapy for exacerbations is not justified and alternative approaches should be adapted.

Inhaled Antibiotic Delivery Systems— Innovations There has been an increase in the variety of delivery devices available for the administration of antibiotics over recent years with advances in inhaled drug delivery technology. The optimal delivery device generates an aerosol of antibiotics in the respirable range with small diameter particles (

Aerosolized antibiotics for non-cystic fibrosis bronchiectasis.

Evidence of inhaled tobramycin in non-cystic fibrosis bronchiectasis.

Cystic fibrosis and non-cystic fibrosis bronchiectasis.

Fungi in cystic fibrosis and non-cystic fibrosis bronchiectasis.

Nontuberculous mycobacteria in cystic fibrosis and non-cystic fibrosis bronchiectasis.

Imaging in cystic fibrosis and non-cystic fibrosis bronchiectasis.

Two cases of non-cystic fibrosis (CF) bronchiectasis with allergic bronchopulmonary aspergillosis.

Global impact of bronchiectasis and cystic fibrosis.

Defining severity in non-cystic fibrosis bronchiectasis.

[Non-cystic fibrosis bronchiectasis: diagnosis and treatment].

Inhaled mannitol for non-cystic fibrosis bronchiectasis: a randomised, controlled trial.

Inhaled corticosteroids for cystic fibrosis.

Statins for non-cystic fibrosis bronchiectasis.

Antimicrobial treatment of non-cystic fibrosis bronchiectasis.

Airway clearance strategies in cystic fibrosis and non-cystic fibrosis bronchiectasis.

The microbiome and emerging pathogens in cystic fibrosis and non-cystic fibrosis bronchiectasis.

Inhaled Antibiotics for Refractory Nontuberculous Mycobacteria and Non-Cystic Fibrosis Bronchiectasis and the Significance of Mycobacterium abscessus subsp. abscessus Isolation during M. avium Complex Lung Disease Therapy.

Use of inhaled tobramycin in cystic fibrosis.

Role of vitamin D in cystic fibrosis and non-cystic fibrosis bronchiectasis.

Candida albicans chronic colonisation in cystic fibrosis may be associated with inhaled antibiotics.

Evaluation of tests to predict metallo-β-lactamase in cystic fibrosis (CF) and non-(CF) Pseudomonas.

Cystic fibrosis, intravenous antibiotics, and home therapy.

Children with recurrent pneumonia and non-cystic fibrosis bronchiectasis.

Breakthrough therapies: Cystic fibrosis (CF) potentiators and correctors.