Thematic Review Series Vol. 88, 2014 Respiration 2014;88:177–184 DOI: 10.1159/000366000
Published online: August 22, 2014
Aerosolized Antibiotics for Non-Cystic Fibrosis Bronchiectasis Bruce K. Rubin b Ronald W. Williams a a
Division of Pulmonary Medicine at b Department of Pediatrics, Virginia Commonwealth University School of Medicine, Children’s Hospital of Richmond at VCU, Richmond, Va., USA
Abstract Patients with non-cystic fibrosis bronchiectasis (NCFB) share many of the respiratory symptoms and the disease progression of cystic fibrosis (CF). As there are no approved therapies for the management of NCFB, an approach has been to use therapies similar to those used to treat CF. In many cases, however, this is ineffective or detrimental. The reason for this has not been determined, but it may be due to key differences in pathogenesis. The questions arising from this have spurred dedicated investigation into the effective management of NCFB. Patients with NCFB have chronic bacterial infection, and bacterial load correlates with symptoms and quality of life. Treatment with systemic antibiotics decreases bacterial load and can have a favorable effect on outcomes. Chronic or frequent use of systemic antibiotics, however, is impractical and sometimes unsafe, so aerosol as a means of delivery is seen as an attractive alternative. The clinical response to and tolerability of inhaled antibiotics have differed significantly between NCFB and CF. New delivery technology, novel antibiotic formulations and a better understanding of the bacterial burden of NCFB are now changing the approach to disease management. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 0025–7931/14/0883–0177$39.50/0 E-Mail [email protected] www.karger.com/res
Introduction
Bronchiectasis is a pathological condition whereby the walls of the airways become progressively weakened due to repeated injury and obstruction. Damage is cumulative and results in abnormally dilated and thickened bronchial walls. Clinical manifestations vary from patients being asymptomatic to experiencing symptoms daily. The most common symptoms are nonspecific and include cough, sputum expectoration and lethargy, while more severe manifestations include hemoptysis, chest pain, shortness of breath and decreased exercise tolerance [1]. The conditions associated with the development of bronchiectasis are broadly categorized as postinfectious damage, abnormal host defenses, genetic defects, congenital malformations, mechanical obstruction, chronic inflammatory conditions and autoimmune disease. In at least half the cases, however, a cause cannot be determined [2–5]. The vicious cycle hypothesis posits that inflammation predisposes to chronic infection (called chronic suppurative lung disease) with the host response contributing to airway damage, which then sustains the inflammation [1, 6]. Previous articles in this series: 1. Usmani OS: New developments in inhaled drugs: within and beyond the lungs. Respiration 2014;88:1–2. 2. Lavorini F, Fontana GA, Usmani OS: New inhaler devices – the good, the bad and the ugly. Respiration 2014;88:3–15.
Ronald W. Williams, MD Division of Pulmonary Medicine, Department of Pediatrics Virginia Commonwealth University School of Medicine Children’s Hospital of Richmond at VCU, PO Box 980315, Richmond, VA 23298 (USA) E-Mail rwwilliams @ vcu.edu
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Key Words Bronchiectasis · Aerosols · Antibiotic resistance · Cystic fibrosis
Though not the most common cause of bronchiectasis, cystic fibrosis (CF) is perhaps the best-studied. The pathogenesis of bronchiectasis in CF stems from a genetic abnormality that predisposes to chronic lung infection and a persistent inflammatory state within the lung. The progression of lung damage and the development of bronchiectasis in CF closely match the vicious cycle hypothesis; this is used as a starting point for therapy in non-CF bronchiectasis (NCFB) [7].
Problems Arise because NCFB Is Not CF
Despite having common symptoms, therapies effective for the treatment of CF have not always been beneficial in treating NCFB [7]. The use of nebulized dornase alfa has not only been unhelpful, but even harmful and associated with increased frequency of exacerbations and an accelerated decline in lung function [8–10]. Another mainstay of therapy for CF lung disease is tobramycin solution for inhalation, but results have been disappointing when using it for NCFB [7], with study patients more likely to report cough, dyspnea, wheezing and chest pain than those on a placebo. There was also no improvement in measured lung function [11]. The great heterogeneity among the conditions called NCFB may be impeding the development of effective therapies. No animal model has been found to be adequate, so basic scientific research is limited [7]. Furthermore, populations of patients are often too small for clinical investigations to produce generalizable results [12]. Interpretation of results can also be difficult because there is no standard approach to diagnosing an exacerbation of NCFB lung disease as there is in CF [13, 14]. Correlations between low FEV1, dyspnea and increased mortality have been reported [13]. Factors contributing to/associated with these include increased cough and sputum expectoration, wheezing, declining exercise tolerance, chest X-ray changes and pathological chest sounds, with some or all of these often being used to qualify an exacerbation [15–17]. Studies on children have reached similar conclusions, with an exacerbation being closely correlated with a wet cough and worsening cough severity, while spirometry may be less helpful [18].
the vicious cycle hypothesis, inflammation is a key contributor to the development and progression of NCFB. Antibiotics are routinely employed in treatment due to the increasing evidence supporting the role of bacteria in promoting and continuing inflammation [19, 20] and likely a direct correlation between bacterial load and both airway and systemic inflammation [6, 13, 21, 22] (even though this does not always correlate with clinical outcomes [7, 23]). An understanding of the microbial milieu in CF lung disease has grown over decades and continues to evolve, and it seems that similar organisms are associated with NCFB [10]. NCFB patients frequently harbor Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus and Moraxella catarrhalis [14, 22, 24], and although Aspergillus and nontubercular Mycobacterium have not been investigated as thoroughly, the evidence available suggests that these are sometimes discovered in NCFB [3, 22, 25]. An exception may be the Lady Windermere syndrome, though this is increasingly associated with CFTR gene mutations [26, 27]. The role of individual bacteria in the pathogenesis of NCFB has not been clearly established. P. aeruginosa is found in approximately 25% of patients with NCFB [28], and it has been associated with more frequent exacerbations, faster disease progression and increased mortality [20, 22, 24, 29, 30]. The number of clinical trials investigating antibiotic therapy in NCFB is small [12, 23]. Azithromycin and other macrolides are some of the more thoroughly investigated drugs for NCFB [12], and evidence is accumulating that such treatment can improve both microbiological and clinical outcomes [12, 31]. Investigations into both long- and short-term use of other systemic antibiotics have produced conflicting results; they suggest that treatment does reduce bacterial load but they do not conclusively show significant clinical benefit [32–34]. Advances in aerosol delivery in recent years have shifted the focus of research to inhaled antibiotic therapy for NCFB, but the early results are conflicting, showing less benefit than expected compared to the results in CF patients [33].
Aerosols Delivering High Concentrations of Antibiotics Approach to Treatment
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The advantages of inhaled medication delivery have been well described. Irrespective of the medical condition, a key limitation for its use has been the difficulty of safely achieving therapeutic drug levels within the lung. Rubin /Williams
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Currently, no medications have been approved for the treatment of NCFB in the USA [7], but from a practical standpoint, treatment must still be provided. Following
Antibiotics under Investigation for Aerosol Delivery in NCFB
Novel formulations and aerosolized antibiotic formulations already approved for use in CF are being investigated specifically for use in NCFB. Tobramycin Tobramycin is widely used for inhalation therapy to treat CF lung disease. It is currently available in a liquid form for nebulization and as a dry powder for inhalation. It is also the most-studied inhaled antibiotic for use in NCFB. Results in patients infected with P. aeruginosa have generally been consistent. In NCFB, inhaled tobramycin, with or without other antibiotics, reduces bacterial density on culture but fails to improve lung function or quality of life measurements [11, 38–40]. One openlabel and uncontrolled study that followed only symptom and quality of life scores reported an improvement after three cycles of therapy [41]. All the studies have reported that inhaled tobramycin is frequently not tolerated well in this patient population [10, 20]. Aztreonam Inhaled aztreonam is currently approved for use in CF lung disease. To date, there has been little investigation into its use in NCFB. The results of the AIR-BX1 and Aerosolized Antibiotics for NCFB
AIR-BX2 trials were presented in 2013, but these did not show any clinical benefit based on symptom scores and time to exacerbation [42]. Colistin Nebulized colistin has primarily been studied in the context of CF lung disease, but has also been investigated for use with ventilator-associated pneumonia and, in a limited capacity, for NCFB. Though it is generally welltolerated, no study has been able to deliver significantly impressive results. There is also no agreement on the optimal dose, as the pharmacokinetic and pharmacodynamic properties of the inhaled form have not been determined. As such, inhaled colistin has not gained FDA approval, and its use remains off-label [43]. Investigations targeting NCFB have mostly reported improvements in quality of life, although in one study, these data were collected retrospectively [44] and in another, this was a secondary end point [20]. One study reported that colistin use slowed the decline of FEV1 [44], but others found no change [20, 45]. Each study reported longer times to exacerbation while using colistin [20, 44, 45]. Gentamicin There has been limited investigation into the use of nebulized gentamicin in NCFB, but early results were favorable. A year-long study showed that its use led to significant reductions in sputum bacterial density and markers of airway inflammation and improvements in exercise tolerance and patient-reported quality of life [46]. Ciprofloxacin With promising early results and the availability of different formulations, ciprofloxacin appears to be the most actively investigated drug for use in NCFB. The ORBIT (Once-Daily Respiratory Bronchiectasis Inhalation Treatment) studies are investigating liposomal ciprofloxacin for inhalation. Two formulations are under investigation: ARD-3100 (LipoquinTM, Aradigm Corp., Hayward, Calif., USA) is a liposomal formulation and ARD-3150 (PulmaquinTM, Aradigm Corp.) is a dual-release mixture of ARD-3100 with unencapsulated ciprofloxacin. ORBIT-1, a phase IIB study, showed that Lipoquin use resulted in a significant decrease in P. aeruginosa growth from sputum culture, and that the medicine was very well tolerated [47]. Another phase IIB study, ORBIT-2, showed similar efficacy and tolerability with Pulmaquin and a greater time to exacerbation [17]. ORBIT-3 and ORBIT-4, both phase III studies, will investigate the time Respiration 2014;88:177–184 DOI: 10.1159/000366000
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Improvements in nebulizer technology have greatly increased delivery efficiency, which is approximately 10% of the loading dose with conventional nebulizers [35]. Newer systems like eFlow® (PARI Pharma GmbH, Munich, Germany), I-neb AAD (Adaptive Aerosol Delivery; Philips Respironics, Chichester, UK) and AKITA2 APIXNEBTM and FOXTM (Vectura, Chippenham, UK) are able to achieve >70% delivery efficiency in some settings [36]. There are continuing improvements in drug design, with the emergence of aerosolized formulations that are well tolerated at the epithelial surface, able to penetrate infected sputum and capable of evading immune system clearance long enough to achieve a therapeutic response [33]. The antibiotics chosen for study are often those with concentration-dependent effects, i.e. a greater AUC/MIC ratio improves killing, as it is possible to achieve very high concentrations of the drug in the airway without the corresponding systemic side effects; this is advantageous for overcoming bacterial resistance [14, 34, 37].
8
Baseline ciprofloxacin DPI
p < 0.001
7
EOT ciprofloxacin DPI p = 0.062
Baseline placebo
p = 0.267
EOT placebo
p = 0.001
3 2
Levofloxacin Pulmatrix Inc. (Lexington, Mass., USA) is developing a dry powder formulation of levofloxacin (PUR0400) using novel iSPERSETM (inhaled small particles easily respirable and emittable) technology. Its use is envisioned for 180
Respiration 2014;88:177–184 DOI: 10.1159/000366000
M. catarrhalis
S. pneumoniae
Bacteria
CF and NCFB, but it is still in preclinical development [54]. Updated information on its physical and aerosol properties and the stability of the product was presented at the 2014 Respiratory Drug Delivery Conference. Amikacin Liposomal formulations of amikacin have been investigated for the treatment of P. aeruginosa infection in CF and nontubercular Mycobacterium with promising early results. A phase III study for use in NCFB is ongoing [55].
Antibiotic Enhancers
There is great interest in adjuncts that improve antibiotic activity, increase retention within the lung and reduce cytotoxicity. Many are in preclinical investigations for use in CF, and are being viewed as likely candidates for treating NCFB. Certain metals are known to have antimicrobial properties and have shown promise in the treatment of lung infection, especially by P. aeruginosa. Studies in vitro have shown that bismuth interferes with biofilm production [56] and that, when encapsulated with tobramycin within Rubin /Williams
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to first pulmonary exacerbation, safety and efficacy in NCFB patients chronically infected with P. aeruginosa [48, 49]. Bayer has developed ciprofloxacin for dry powder inhalation (DPI) using PulmoSphereTM technology (Novartis) that is also being investigated for use in NCFB. Results for a phase II study show that twice-daily use for 28 days yields a statistically significant reduction in bacterial load [50]. As opposed to the ORBIT studies which limited their surveillance to P. aeruginosa, this study tracked all organisms and demonstrated efficacy against mucoid P. aeruginosa, S. pneumoniae, H. influenzae and M. catarrhalis (fig. 1). Two phase III studies, RESPIRE 1 and RESPIRE 2, are ongoing and will continue to investigate clinical efficacy and safety of ciprofloxacin DPI [51, 52]. In April 2014, this formulation was granted orphan drug designation for use in NCFB by the Food and Drug Administration in the USA [53].
S. aureus
0
H. influenzae
1
P. aeruginosa (nonmucoid)
pathogens at baseline and at end of treatment. Only results from valid cultures were considered. Cultures were excluded if subjects were administered concomitant antibacterials, if there were >25 squamous epithelial cells in the absence of P. aeruginosa or if there were ≤25 leukocytes for P. aeruginosa-negative cultures pretherapy. Reproduced with the permission of the European Respiratory Society [50]. EOT = End of treatment.
p = 0.438
4
P. aeruginosa (mucoid)
Fig. 1. Mean colony count of selected
p = 0.093
p = 0.880
5
Total bacterial load
Bacterial load (log10 CFU/g)
6
Table 1. Reported development of resistance after use of aerosolized antibiotics in NCFB N (n)a
Drug
Study type
Population
Colistin
prospective
NCFB and COPD
Colistin Gentamicin Tobramycin
R, PC R, PC DB, PC, crossover
NCFB with PA NCFB NCFB with PA
144 (73) 65 (27) 20 (20)
Tobramycin
OL
NCFB with PA
31 (31)
none none 10%b (to drug, to placebo) 6%
Ciprofloxacin (DRCFI)
phase II DB, R, PC
NCFB with PA
37 (18)
none
Ciprofloxacin (DPI)
phase II DB, R, PC
NCFB with positive 124 (60) culture
10%b
18 (18)
Resistance
Duration
Reference, first author
none
once daily for an average of 41 months twice daily for up to 6 months twice daily for 12 months twice daily for 6 months
[44] Steinfort, 2007
twice daily 14 days on/off for 12 weeks once daily 28 days on/off for 24 weeks twice daily for 28 days
[41] Scheinberg, 2005
[20] Haworth, 2014 [46] Murray, 2011 [39] Drobnic, 2004
[17] Serisier, 2013 [50] Wilson, 2013
DB = Double-blind; DRCFI = dual-release ciprofloxacin for inhalation; OL = open-label; PA = P. aeruginosa; PC = placebo-controlled; R = randomized. a Number of patients who completed the study (number on the drug). b Resistance lost after stopping therapy
a liposome, can increase antibiotic efficacy against common respiratory pathogens [57]. This formulation is able to penetrate CF sputum [58] and has shown antibiotic effectiveness at lower concentrations with improved targeting [59]. In addition to biofilm effects, there is also an interruption of quorum sensing, signaling molecule production and a decreased secretion of virulence factors [60]. In vitro investigations with gallium using CF sputum have identified a disruption of iron metabolism that prevents biofilm production and retards the growth of P. aeruginosa [61]. A liposomal formulation of gallium and gentamicin has also shown greater antibiotic efficacy than the use of gentamicin alone against P. aeruginosa growing in a biofilm in CF sputum [62]. Liposomal formulations are attractive in NCFB because they can be effectively aerosolized. They also offer the advantage of reducing the cytotoxicity of the encapsulated products by improving delivery, which allows reduced dosing [58, 62, 63]. Dosing reduction is also facilitated by surface modification of the lysosomes, i.e. PEGylation, which helps avoid immune system recognition and delays clearance [64]. Combination antibiotic therapy is also an area of active investigation, possessing the advantages of a broadened spectrum of activity, an improved efficiency of administration and synergistic antimicrobial effects which allow for reduced dosing. A combination of fosfomycin and tobramycin has shown efficacy in vitro against respiratory pathogens common in CF and NCFB [65, 66] and has been administered as an aerosol to adults with CF in early clinical trials [67]. This combination has also demonstrated synergistic bactericidal effects and eradicated P.
aeruginosa biofilms in vitro [68]. Aerosol delivery of a combination of amikacin and fosfomycin has been shown to achieve adequate drug concentrations in intubated patients with ventilator-associated pneumonia without adverse effects, although the clinical response here was not actually reported [69]. There has also been a demonstration of synergy with a combination of colistin and tobramycin in vitro, in a rat model and in an early clinical trial with CF patients [70].
Aerosolized Antibiotics for NCFB
Respiration 2014;88:177–184 DOI: 10.1159/000366000
Emergence of Bacterial Resistance
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With aerosol delivery, antibiotic concentrations in the proximal airway can greatly exceed those obtained safely by other means [71]. There is an advantage to delivering antibiotics that have greater efficacy at higher AUC/MIC ratios, as this can help to overcome efflux pump-driven bacterial resistance [33, 71]. Unfortunately, aerosol delivery to the lung is not uniform, and this has the potential to create antibiotic concentration gradients, i.e. much lower concentrations are found in deeper parts of the lung [33]. Continued subtherapeutic exposure allows bacterial adaptation and fosters the development of resistance [72]. It is now recognized that most of the bacteria associated with chronic infection in CF, NCFB and other conditions are capable of biofilm formation. In addition to providing barrier protection against antibiotics, this also establishes a sustained, protected environment that allows for lateral gene exchange and increases the likelihood of organisms acquiring more resistance [73].
Table 2. Active clinical trials, as of June 2014, studying aerosolized antibiotics for use in NCFB
Study
Phase
Identifier
Status
Pulmaquin in NCFB (ORBIT-4)
III
NCT02104245
Not yet recruiting
Dual-release ciprofloxacin for inhalation in NCFB (ORBIT-3)
III
NCT01515007
Recruiting
Ciprofloxacin DPI in NCFB (RESPIRE 1)
III
NCT01764841
Recruiting
Ciprofloxacin DPI in NCFB (RESPIRE 2)
III
NCT02106832
Recruiting
Combined administration of nebulized amikacin in patients with acute exacerbation of NCFB
III
NCT02081963
Ongoing but not recruiting
Efficacy and tolerability of the tobramycin podhaler in bronchiectasis patients with chronic P. aeruginosa infection (TOBI)
N/S
NCT02102152
Not yet recruiting
Pharmacokinetic evaluation and tolerability of dry powder tobramycin by a novel device in patients with NCFB
I, II
NCT02035488
Recruiting
Source: ClinicalTrials.gov. N/S = Not specified.
References
Discussion
Increasing recognition of the prevalence and burden of NCFB has spurred research into its epidemiology, pathogenesis and management. It is clear, despite the variety of causes, that NCFB is sufficiently distinct in many ways from CF, and that a default approach of using therapies proven in CF is not adequate and is even potential182
ly counterproductive. Antibiotic therapy for acute and chronic infections has shown variable results. Treatment clearly reduces bacterial load as well as symptoms like cough and sputum expectoration to the point that improvements in the quality of life of patients have been demonstrated. Preferred antibiotics and routes of delivery for management have not been established. There is growing interest in pursuing aerosol delivery because of its convenience and lower side-effect profiles, although admittedly, this has been biased due to the demonstrated successes with CF. Technological advancements in aerosolization and drug development have enabled investigation of novel therapies and the initial results are promising, with different formulations of ciprofloxacin and amikacin entering phase III trials. Alternative formulations of inhaled tobramycin, which may prove to be better-tolerated, are at the stage of early clinical trials (table 2). It is too early to speculate on the efficacy and cost benefits of therapy.
Respiration 2014;88:177–184 DOI: 10.1159/000366000
1 Goeminne P, Dupont L: Non-cystic fibrosis bronchiectasis: diagnosis and management in 21st century. Postgrad Med J 2010; 86: 493– 501. 2 Cohen M, Sahn SA: Bronchiectasis in systemic diseases. Chest 1999;116:1063–1074. 3 Pasteur MC, Helliwell SM, Houghton SJ, Webb SC, Foweraker JE, Coulden RA, et al: An investigation into causative factors in patients with bronchiectasis. Am J Respir Crit Care Med 2000;162:1277–1284.
Rubin /Williams
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There is a growing understanding of the microenvironment within the CF lung, and particularly its role in the development of antibiotic resistance. In CF treatment, there have been limited reports of acquired resistance to tobramycin [74], but this is usually sustained for only a few months after stopping therapy [34]. There have also been reports of acquired resistance to aztreonam when used twice daily, but not when used 3 times a day [75]. Acquired resistance to colistin is rare [76]. While investigations to date have not identified a clinically relevant resistance to inhaled antibiotics in CF [77], concerns remain that continued and more widespread use will increase the risk of developing resistance [10]. There are known differences in antibiotic activity between the CF and non-CF lung, particularly with aminoglycosides and fluoroquinolones [71, 78], and this may change adaptation pressure. Outcomes in NCFB, however, appear similar to those in CF, including a likely loss of resistance after stopping therapy [50]. Our results are summarized in table 1.
Aerosolized Antibiotics for NCFB
18 Kapur N, Masters IB, Morris PS, Galligan J, Ware R, Chang AB: Defining pulmonary exacerbation in children with non-cystic fibrosis bronchiectasis. Pediatr Pulmonol 2012;47: 68–75. 19 Cole PJ: Inflammation: a two-edged sword – the model of bronchiectasis. Eur J Respir Dis Suppl 1986;147:6–15. 20 Haworth CS, Foweraker JE, Wilkinson P, Kenyon RF, Bilton D: Inhaled colistin in patients with bronchiectasis and chronic Pseudomonas aeruginosa infection. Am J Respir Crit Care Med 2014;189:975–982. 21 Angrill J, Agustí C, de Celis R, Filella X, Rañó A, Elena M, et al: Bronchial inflammation and colonization in patients with clinically stable bronchiectasis. Am J Respir Crit Care Med 2001;164:1628–1632. 22 Kapur N, Grimwood K, Masters IB, Morris PS, Chang AB: Lower airway microbiology and cellularity in children with newly diagnosed non-CF bronchiectasis. Pediatr Pulmonol 2012;47:300–307. 23 Chang AB, Bilton D: Exacerbations in cystic fibrosis. 4. Non-cystic fibrosis bronchiectasis. Thorax 2008;63:269–276. 24 Rogers GB, van der Gast CJ, Cuthbertson L, Thomson SK, Bruce KD, Martin ML, et al: Clinical measures of disease in adult non-CF bronchiectasis correlate with airway microbiota composition. Thorax 2013;68:731–737. 25 Seitz AE, Olivier KN, Steiner CA, Montes de Oca R, Holland SM, Prevots DR: Trends and burden of bronchiectasis-associated hospitalizations in the United States, 1993–2006. Chest 2010;138:944–949. 26 Rubin BK: Did Lady Windermere have cystic fibrosis? Chest 2006;130:937–938. 27 Sexton P, Harrison AC: Susceptibility to nontuberculous mycobacterial lung disease. Eur Respir J 2008;31:1322–1333. 28 Rademacher J, Welte T: Bronchiectasis – diagnosis and treatment. Dtsch Ärztebl Int 2011;108:809–815. 29 Martínez-García MÁ, Soler Cataluña JJ, Perpiñá-Tordera M, Román-Sánchez P, Soriano J: Factors associated with lung function decline in adult patients with stable non-cystic fibrosis bronchiectasis. Chest 2007;132:1565– 1572. 30 King PT, Holdsworth SR, Freezer NJ, Villanueva E, Holmes PW: Microbiologic followup study in adult bronchiectasis. Respir Med 2007;101:1633–1638. 31 Wong C, Jayaram L, Karalus N, Eaton T, Tong C, Hockey H, et al: Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet 2012;380:660–667. 32 Evans DJ, Greenstone M: Long-term antibiotics in the management of non-CF bronchiectasis – do they improve outcome? Respir Med 2003;97:851–858. 33 Rubin BK: Aerosolized antibiotics for noncystic fibrosis bronchiectasis. J Aerosol Med Pulm D 2008;21:71–76.
34 Martínez-García MÁ, Máiz Carro L, CatalánSerra P: Treatment of non-cystic fibrosis bronchiectasis. Archiv Bronconeumol 2011; 47:599–609. 35 Hanif SNM, Garcia-Contreras L: Pharmaceutical aerosols for the treatment and prevention of tuberculosis. Front Cell Infect Microbiol 2012;2:118. 36 Nikander K, Prince I, Coughlin S, Warren S, Taylor G: Mode of breathing – tidal or slow and deep – through the I-neb Adaptive Aerosol Delivery (AAD) System affects lung deposition of 99mTc-DTPA. J Aerosol Med Pulm D 2010;23:S-37–S-43. 37 Morosini MI, García-Castillo M, Loza E, Pérez-Vázquez M, Baquero F, Cantón R: Breakpoints for predicting Pseudomonas aeruginosa susceptibility to inhaled tobramycin in cystic fibrosis patients: use of high-range Etest strips. J Clin Microbiol 2005; 43: 4480– 4485. 38 Couch LA: Treatment with tobramycin solution for inhalation in bronchiectasis patients with Pseudomonas aeruginosa. Chest 2001; 120:114S–117S. 39 Drobnic ME: Inhaled tobramycin in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection with Pseudomonas aeruginosa. Ann Pharmacother 2004; 39: 39–44. 40 Bilton D, Henig N, Morrissey B, Gotfried M: Addition of inhaled tobramycin to ciprofloxacin for acute exacerbations of Pseudomonas aeruginosa infection in adult bronchiectasis. Chest 2006;130:1503–1510. 41 Scheinberg P, Shore E: A pilot study of the safety and efficacy of tobramycin solution for inhalation in patients with severe bronchiectasis. Chest 2005;127:1420–1426. 42 Barker A, O’Donnell A, Thompson P, et al: Two phase 3 placebo-controlled trials of aztreonam lysine for inhalation (AZLI) for noncystic fibrosis bronchiectasis (NCFB). Eur Respir J 2013;42(suppl 57):4136. 43 Michalopoulos A, Papadakis E: Inhaled antiinfective agents: emphasis on colistin. Infection 2010;38:81–88. 44 Steinfort DP, Steinfort C: Effect of long-term nebulized colistin on lung function and quality of life in patients with chronic bronchial sepsis. Intern Med J 2007;37:495–498. 45 Dhar R, Anwar GA, Bourke SC, Doherty L, Middleton P, Ward C, et al: Efficacy of nebulised colomycin in patients with non-cystic fibrosis bronchiectasis colonised with Pseudomonas aeruginosa. Thorax 2010; 65: 553– 553. 46 Murray MP, Govan JRW, Doherty CJ, Simpson AJ, Wilkinson TS, Chalmers JD, et al: A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2011; 183: 491– 499.
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4 Fuschillo S, De Felice A, Balzano G: Mucosal inflammation in idiopathic bronchiectasis: cellular and molecular mechanisms. Eur Respir J 2008;31:396–406. 5 De Soyza A, Brown JS, Loebinger MR; Bronchiectasis Research and Academic Network: Research priorities in bronchiectasis. Thorax 2013;68:695–696. 6 Short- and long-term antibiotic treatment reduces airway and systemic inflammation in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2012;186:657–665. 7 Metersky ML, O’Donnell AE: Nebulized colistin for non-cystic fibrosis bronchiectasis: déjà vu all over again? Am J Respir Crit Care Med 2014;189:1151–1152. 8 Wills PJ, Wodehouse T, Corkery K, Mallon K, Wilson R, Cole PJ: Short-term recombinant human DNase in bronchiectasis. Effect on clinical state and in vitro sputum transportability. Am J Respir Crit Care Med 1996;154: 413–417. 9 O’Donnell AE, Barker AF, Ilowite JS, Fick RB: Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase I. rhDNase Study Group. Chest 1998;113:1329– 1334. 10 Serisier DJ: The evidence base for non-CF bronchiectasis is finally evolving. Respirology 2014;19:295–297. 11 Barker AF, Couch L, Fiel SB, Gotfried MH, Ilowite J, Meyer KC, et al: Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis. Am J Respir Crit Care Med 2000; 162: 481– 485. 12 Feldman C: Bronchiectasis: new approaches to diagnosis and management. Clin Chest Med 2011;32:535–546. 13 McShane PJ, Naureckas ET, Tino G, Strek ME: Non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2013;188:647–656. 14 Amorim A, Gamboa F, Azevedo P: New advances in the therapy of non-cystic fibrosis bronchiectasis. Rev Port Pneumol 2013; 19: 266–275. 15 Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al: Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med 1994;331:637–642. 16 Vendrell M, de Gracia J, Olveira C, Martínez MA, Girón R, Máiz L, et al: Diagnosis and treatment of bronchiectasis. Spanish Society of Pneumology and Thoracic Surgery. Arch Bronconeumol 2008;44:629–640. 17 Serisier DJ, Bilton D, De Soyza A, Thompson PJ, Kolbe J, Greville HW, et al: Inhaled, dualrelease liposomal ciprofloxacin in non-cystic fibrosis bronchiectasis (ORBIT-2): a randomised, double-blind, placebo-controlled trial. Thorax 2013;68:812–817.
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58 Halwani M, Hebert S, Suntres ZE, Lafrenie RM, Azghani AO, Omri A: Bismuth-thiol incorporation enhances biological activities of liposomal tobramycin against bacterial biofilm and quorum-sensing molecules production by Pseudomonas aeruginosa. Int J Pharmaceut 2009;373:141–146. 59 Alipour M, Suntres ZE, Lafrenie RM, Omri A: Attenuation of Pseudomonas aeruginosa virulence factors and biofilms by co-encapsulation of bismuth-ethanedithiol with tobramycin in liposomes. J Antimicrob Chemother 2010;65:684–693. 60 Alhariri M, Omri A: Efficacy of liposomal bismuth-ethanedithiol-loaded tobramycin after intratracheal administration in rats with pulmonary Pseudomonas aeruginosa infection. Antimicrob Agents Chemother 2013;57:569– 578. 61 Kaneko Y, Thoendel M, Olakanmi O, Britigan BE, Singh PK: The transition metal gallium disrupts Pseudomonas aeruginosa iron metabolism and has antimicrobial and antibiofilm activity. J Clin Invest 2007;117:877–888. 62 Halwani M, Yebio B, Suntres ZE, Alipour M, Azghani AO, Omri A: Co-encapsulation of gallium with gentamicin in liposomes enhances antimicrobial activity of gentamicin against Pseudomonas aeruginosa. J Antimicrob Chemother 2008;62:1291–1297. 63 Alhajlan M, Alhariri M, Omri A: Efficacy and safety of liposomal clarithromycin and its effect on Pseudomonas aeruginosa virulence factors. Antimicrob Agents Chemother 2013; 57:2694–2704. 64 Chono S, Suzuki H, Togami K, Morimoto K: Efficient drug delivery to lung epithelial lining fluid by aerosolization of ciprofloxacin incorporated into PEGylated liposomes for treatment of respiratory infections. Drug Dev Ind Pharm 2011;37:367–372. 65 MacLeod DL, Barker LM, Sutherland JL, Moss SC, Gurgel JL, Kenney TF, et al: Antibacterial activities of a fosfomycin/tobramycin combination: a novel inhaled antibiotic for bronchiectasis. J Antimicrob Chemother 2009;64:829–836. 66 McCaughey G, McKevitt M, Elborn JS, Tunney MM: Antimicrobial activity of fosfomycin and tobramycin in combination against cystic fibrosis pathogens under aerobic and anaerobic conditions. J Cyst Fibros 2012; 11: 163–172. 67 Trapnell BC, McColley SA, Kissner DG, Rolfe MW, Rosen JM, McKevitt M, et al: Fosfomycin/tobramycin for inhalation in patients with cystic fibrosis with Pseudomonas airway infection. Am J Respir Crit Care Med 2012;185: 171–178.
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68 Anderson GG, Kenney TF, MacLeod DL, Henig NR, O’Toole GA: Eradication of Pseudomonas aeruginosa biofilms on cultured airway cells by a fosfomycin/tobramycin antibiotic combination. Pathog Dis 2013;67:39–45. 69 Montgomery AB, Vallance S, Abuan T, Tservistas M, Davies A: A Randomized doubleblind placebo-controlled dose-escalation phase 1 study of aerosolized amikacin and fosfomycin delivered via the PARI Investigational eFlow® Inline Nebulizer System in mechanically ventilated patients. J Aerosol Med Pulm Drug Deliv 2014;27:1–8. 70 Herrmann G, Yang L, Wu H, Song Z, Wang H, Høiby N, et al: Colistin-tobramycin combinations are superior to monotherapy concerning the killing of biofilm Pseudomonas aeruginosa. J Infect Dis 2010;202:1585–1592. 71 Dudley MN, Loutit J, Griffith DC: Aerosol antibiotics: considerations in pharmacological and clinical evaluation. Curr Opin Biotechnol 2008;19:637–643. 72 Falagas ME, Bliziotis IA, Kasiakou SK, Samonis G, Athanassopoulou P, Michalopoulos A: Outcome of infections due to pandrug-resistant (PDR) Gram-negative bacteria. BMC Infect Dis 2005;5:24. 73 Delissalde F, Amábile-Cuevas CF: Comparison of antibiotic susceptibility and plasmid content, between biofilm producing and nonproducing clinical isolates of Pseudomonas aeruginosa. Int J Antimicrob Agents 2004;24: 405–408. 74 Ryan G, Singh M, Dwan K: Inhaled antibiotics for long-term therapy in cystic fibrosis (review). Cochrane Database Syst Rev 2011; CD001021. 75 Oermann CM, McCoy KS, Retsch-Bogart GZ, Gibson RL, McKevitt M, Montgomery AB: Pseudomonas aeruginosa antibiotic susceptibility during long-term use of aztreonam for inhalation solution (AZLI). J Antimicrob Chemother 2011;66:2398–2404. 76 Conway DSP, Brownlee KG, Denton M, Peckham DG: Antibiotic treatment of multidrug-resistant organisms in cystic fibrosis. Am J Respir Med 2003;2:321–332. 77 Conway DS: Nebulized antibiotic therapy: the evidence. Chron Respir Dis 2005;2:35–41. 78 Hunt BE, Weber A, Berger A, Ramsey B, Smith AL: Macromolecular mechanisms of sputum inhibition of tobramycin activity. Antimicrob Agents Chemother 1995; 39: 34– 39.
Rubin /Williams
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47 Pecota N: Aradigm reports successful ORBIT1 bronchiectasis study with inhaled liposomal ciprofloxacin. http://investor.aradigm.com/ releasedetail.cfm (accessed 17 May 2014). 48 Aradigm Corporation, Grifols Therapeutics Inc: Phase 3 study with dual-release ciprofloxacin for inhalation in non-CF bronchiectasis. http://clinicaltrials.gov/ct2/show/study/ NCT01515007 (accessed 26 May 2014). 49 Aradigm Corporation, Grifols Therapeutics Inc: Phase 3 study with pulmaquin in non-CF bronchiectasis (ORBIT-4). http://clinicaltrials.gov/ct2/show/study/NCT02104245 (accessed 26 May 2014). 50 Wilson R, Welte T, Polverino E, De Soyza A, Greville H, O’Donnell A, et al: Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis: a phase II randomised study. Eur Respir J 2013;41:1107–1115. 51 Bayer, Novartis: Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis (non-CF BE) (RESPIRE 1). http://clinicaltrials.gov/ct2/show/NCT01764841 (accessed 17 May 2014). 52 Bayer, Novartis: Ciprofloxacin dry powder for inhalation (DPI) in non-cystic fibrosis bronchiectasis (non-CF BE) (RESPIRE 2). http://clinicaltrials.gov/ct2/show/NCT02106 832?term=NCT02106832&rank=1 (accessed 17 May 2014). 53 Bayer: FDA grants orphan drug designation for Bayer’s investigational ciprofloxacin DPI (dry powder for inhalation) for treatment of non-cystic fibrosis bronchiectasis. Bayer Healthcare 2014, http://www.pharma.bayer. com/html/pdf/Final-FDA_Grants_Orphan_ Drug_Designation_for_Investigational_Ciprofloxacin_DPI.pdf. 54 Manzanedo D, Brande M, Kramer S, et al: Formulation characterization of a novel levofloxacin pulmonary dry powder drug delivery technology. Respiratory Drug Delivery Conference, Phoenix, 2012, pp 1–4. 55 Qilu Hospital: Combined administration of nebulized amikacin in patients with acute exacerbation of non-cystic fibrosis bronchiectasis. http://clinicaltrials.gov/ct2/show/study/ NCT02081963 (accessed 17 May 2014). 56 Huang CT, Stewart PS: Reduction of polysaccharide production in Pseudomonas aeruginosa biofilms by bismuth dimercaprol (BisBAL) treatment. J Antimicrob Chemother 1999;44:601–605. 57 Halwani M, Blomme S, Suntres ZE, Alipour M, Azghani AO, Kumar A, et al: Liposomal bismuth-ethanedithiol formulation enhances antimicrobial activity of tobramycin. Int J Pharmaceut 2008;358:278–284.
Published online: August 22, 2014
Aerosolized Antibiotics for Non-Cystic Fibrosis Bronchiectasis Bruce K. Rubin b Ronald W. Williams a a
Division of Pulmonary Medicine at b Department of Pediatrics, Virginia Commonwealth University School of Medicine, Children’s Hospital of Richmond at VCU, Richmond, Va., USA
Abstract Patients with non-cystic fibrosis bronchiectasis (NCFB) share many of the respiratory symptoms and the disease progression of cystic fibrosis (CF). As there are no approved therapies for the management of NCFB, an approach has been to use therapies similar to those used to treat CF. In many cases, however, this is ineffective or detrimental. The reason for this has not been determined, but it may be due to key differences in pathogenesis. The questions arising from this have spurred dedicated investigation into the effective management of NCFB. Patients with NCFB have chronic bacterial infection, and bacterial load correlates with symptoms and quality of life. Treatment with systemic antibiotics decreases bacterial load and can have a favorable effect on outcomes. Chronic or frequent use of systemic antibiotics, however, is impractical and sometimes unsafe, so aerosol as a means of delivery is seen as an attractive alternative. The clinical response to and tolerability of inhaled antibiotics have differed significantly between NCFB and CF. New delivery technology, novel antibiotic formulations and a better understanding of the bacterial burden of NCFB are now changing the approach to disease management. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 0025–7931/14/0883–0177$39.50/0 E-Mail [email protected] www.karger.com/res
Introduction
Bronchiectasis is a pathological condition whereby the walls of the airways become progressively weakened due to repeated injury and obstruction. Damage is cumulative and results in abnormally dilated and thickened bronchial walls. Clinical manifestations vary from patients being asymptomatic to experiencing symptoms daily. The most common symptoms are nonspecific and include cough, sputum expectoration and lethargy, while more severe manifestations include hemoptysis, chest pain, shortness of breath and decreased exercise tolerance [1]. The conditions associated with the development of bronchiectasis are broadly categorized as postinfectious damage, abnormal host defenses, genetic defects, congenital malformations, mechanical obstruction, chronic inflammatory conditions and autoimmune disease. In at least half the cases, however, a cause cannot be determined [2–5]. The vicious cycle hypothesis posits that inflammation predisposes to chronic infection (called chronic suppurative lung disease) with the host response contributing to airway damage, which then sustains the inflammation [1, 6]. Previous articles in this series: 1. Usmani OS: New developments in inhaled drugs: within and beyond the lungs. Respiration 2014;88:1–2. 2. Lavorini F, Fontana GA, Usmani OS: New inhaler devices – the good, the bad and the ugly. Respiration 2014;88:3–15.
Ronald W. Williams, MD Division of Pulmonary Medicine, Department of Pediatrics Virginia Commonwealth University School of Medicine Children’s Hospital of Richmond at VCU, PO Box 980315, Richmond, VA 23298 (USA) E-Mail rwwilliams @ vcu.edu
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Key Words Bronchiectasis · Aerosols · Antibiotic resistance · Cystic fibrosis
Though not the most common cause of bronchiectasis, cystic fibrosis (CF) is perhaps the best-studied. The pathogenesis of bronchiectasis in CF stems from a genetic abnormality that predisposes to chronic lung infection and a persistent inflammatory state within the lung. The progression of lung damage and the development of bronchiectasis in CF closely match the vicious cycle hypothesis; this is used as a starting point for therapy in non-CF bronchiectasis (NCFB) [7].
Problems Arise because NCFB Is Not CF
Despite having common symptoms, therapies effective for the treatment of CF have not always been beneficial in treating NCFB [7]. The use of nebulized dornase alfa has not only been unhelpful, but even harmful and associated with increased frequency of exacerbations and an accelerated decline in lung function [8–10]. Another mainstay of therapy for CF lung disease is tobramycin solution for inhalation, but results have been disappointing when using it for NCFB [7], with study patients more likely to report cough, dyspnea, wheezing and chest pain than those on a placebo. There was also no improvement in measured lung function [11]. The great heterogeneity among the conditions called NCFB may be impeding the development of effective therapies. No animal model has been found to be adequate, so basic scientific research is limited [7]. Furthermore, populations of patients are often too small for clinical investigations to produce generalizable results [12]. Interpretation of results can also be difficult because there is no standard approach to diagnosing an exacerbation of NCFB lung disease as there is in CF [13, 14]. Correlations between low FEV1, dyspnea and increased mortality have been reported [13]. Factors contributing to/associated with these include increased cough and sputum expectoration, wheezing, declining exercise tolerance, chest X-ray changes and pathological chest sounds, with some or all of these often being used to qualify an exacerbation [15–17]. Studies on children have reached similar conclusions, with an exacerbation being closely correlated with a wet cough and worsening cough severity, while spirometry may be less helpful [18].
the vicious cycle hypothesis, inflammation is a key contributor to the development and progression of NCFB. Antibiotics are routinely employed in treatment due to the increasing evidence supporting the role of bacteria in promoting and continuing inflammation [19, 20] and likely a direct correlation between bacterial load and both airway and systemic inflammation [6, 13, 21, 22] (even though this does not always correlate with clinical outcomes [7, 23]). An understanding of the microbial milieu in CF lung disease has grown over decades and continues to evolve, and it seems that similar organisms are associated with NCFB [10]. NCFB patients frequently harbor Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus and Moraxella catarrhalis [14, 22, 24], and although Aspergillus and nontubercular Mycobacterium have not been investigated as thoroughly, the evidence available suggests that these are sometimes discovered in NCFB [3, 22, 25]. An exception may be the Lady Windermere syndrome, though this is increasingly associated with CFTR gene mutations [26, 27]. The role of individual bacteria in the pathogenesis of NCFB has not been clearly established. P. aeruginosa is found in approximately 25% of patients with NCFB [28], and it has been associated with more frequent exacerbations, faster disease progression and increased mortality [20, 22, 24, 29, 30]. The number of clinical trials investigating antibiotic therapy in NCFB is small [12, 23]. Azithromycin and other macrolides are some of the more thoroughly investigated drugs for NCFB [12], and evidence is accumulating that such treatment can improve both microbiological and clinical outcomes [12, 31]. Investigations into both long- and short-term use of other systemic antibiotics have produced conflicting results; they suggest that treatment does reduce bacterial load but they do not conclusively show significant clinical benefit [32–34]. Advances in aerosol delivery in recent years have shifted the focus of research to inhaled antibiotic therapy for NCFB, but the early results are conflicting, showing less benefit than expected compared to the results in CF patients [33].
Aerosols Delivering High Concentrations of Antibiotics Approach to Treatment
178
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The advantages of inhaled medication delivery have been well described. Irrespective of the medical condition, a key limitation for its use has been the difficulty of safely achieving therapeutic drug levels within the lung. Rubin /Williams
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Currently, no medications have been approved for the treatment of NCFB in the USA [7], but from a practical standpoint, treatment must still be provided. Following
Antibiotics under Investigation for Aerosol Delivery in NCFB
Novel formulations and aerosolized antibiotic formulations already approved for use in CF are being investigated specifically for use in NCFB. Tobramycin Tobramycin is widely used for inhalation therapy to treat CF lung disease. It is currently available in a liquid form for nebulization and as a dry powder for inhalation. It is also the most-studied inhaled antibiotic for use in NCFB. Results in patients infected with P. aeruginosa have generally been consistent. In NCFB, inhaled tobramycin, with or without other antibiotics, reduces bacterial density on culture but fails to improve lung function or quality of life measurements [11, 38–40]. One openlabel and uncontrolled study that followed only symptom and quality of life scores reported an improvement after three cycles of therapy [41]. All the studies have reported that inhaled tobramycin is frequently not tolerated well in this patient population [10, 20]. Aztreonam Inhaled aztreonam is currently approved for use in CF lung disease. To date, there has been little investigation into its use in NCFB. The results of the AIR-BX1 and Aerosolized Antibiotics for NCFB
AIR-BX2 trials were presented in 2013, but these did not show any clinical benefit based on symptom scores and time to exacerbation [42]. Colistin Nebulized colistin has primarily been studied in the context of CF lung disease, but has also been investigated for use with ventilator-associated pneumonia and, in a limited capacity, for NCFB. Though it is generally welltolerated, no study has been able to deliver significantly impressive results. There is also no agreement on the optimal dose, as the pharmacokinetic and pharmacodynamic properties of the inhaled form have not been determined. As such, inhaled colistin has not gained FDA approval, and its use remains off-label [43]. Investigations targeting NCFB have mostly reported improvements in quality of life, although in one study, these data were collected retrospectively [44] and in another, this was a secondary end point [20]. One study reported that colistin use slowed the decline of FEV1 [44], but others found no change [20, 45]. Each study reported longer times to exacerbation while using colistin [20, 44, 45]. Gentamicin There has been limited investigation into the use of nebulized gentamicin in NCFB, but early results were favorable. A year-long study showed that its use led to significant reductions in sputum bacterial density and markers of airway inflammation and improvements in exercise tolerance and patient-reported quality of life [46]. Ciprofloxacin With promising early results and the availability of different formulations, ciprofloxacin appears to be the most actively investigated drug for use in NCFB. The ORBIT (Once-Daily Respiratory Bronchiectasis Inhalation Treatment) studies are investigating liposomal ciprofloxacin for inhalation. Two formulations are under investigation: ARD-3100 (LipoquinTM, Aradigm Corp., Hayward, Calif., USA) is a liposomal formulation and ARD-3150 (PulmaquinTM, Aradigm Corp.) is a dual-release mixture of ARD-3100 with unencapsulated ciprofloxacin. ORBIT-1, a phase IIB study, showed that Lipoquin use resulted in a significant decrease in P. aeruginosa growth from sputum culture, and that the medicine was very well tolerated [47]. Another phase IIB study, ORBIT-2, showed similar efficacy and tolerability with Pulmaquin and a greater time to exacerbation [17]. ORBIT-3 and ORBIT-4, both phase III studies, will investigate the time Respiration 2014;88:177–184 DOI: 10.1159/000366000
179
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Improvements in nebulizer technology have greatly increased delivery efficiency, which is approximately 10% of the loading dose with conventional nebulizers [35]. Newer systems like eFlow® (PARI Pharma GmbH, Munich, Germany), I-neb AAD (Adaptive Aerosol Delivery; Philips Respironics, Chichester, UK) and AKITA2 APIXNEBTM and FOXTM (Vectura, Chippenham, UK) are able to achieve >70% delivery efficiency in some settings [36]. There are continuing improvements in drug design, with the emergence of aerosolized formulations that are well tolerated at the epithelial surface, able to penetrate infected sputum and capable of evading immune system clearance long enough to achieve a therapeutic response [33]. The antibiotics chosen for study are often those with concentration-dependent effects, i.e. a greater AUC/MIC ratio improves killing, as it is possible to achieve very high concentrations of the drug in the airway without the corresponding systemic side effects; this is advantageous for overcoming bacterial resistance [14, 34, 37].
8
Baseline ciprofloxacin DPI
p < 0.001
7
EOT ciprofloxacin DPI p = 0.062
Baseline placebo
p = 0.267
EOT placebo
p = 0.001
3 2
Levofloxacin Pulmatrix Inc. (Lexington, Mass., USA) is developing a dry powder formulation of levofloxacin (PUR0400) using novel iSPERSETM (inhaled small particles easily respirable and emittable) technology. Its use is envisioned for 180
Respiration 2014;88:177–184 DOI: 10.1159/000366000
M. catarrhalis
S. pneumoniae
Bacteria
CF and NCFB, but it is still in preclinical development [54]. Updated information on its physical and aerosol properties and the stability of the product was presented at the 2014 Respiratory Drug Delivery Conference. Amikacin Liposomal formulations of amikacin have been investigated for the treatment of P. aeruginosa infection in CF and nontubercular Mycobacterium with promising early results. A phase III study for use in NCFB is ongoing [55].
Antibiotic Enhancers
There is great interest in adjuncts that improve antibiotic activity, increase retention within the lung and reduce cytotoxicity. Many are in preclinical investigations for use in CF, and are being viewed as likely candidates for treating NCFB. Certain metals are known to have antimicrobial properties and have shown promise in the treatment of lung infection, especially by P. aeruginosa. Studies in vitro have shown that bismuth interferes with biofilm production [56] and that, when encapsulated with tobramycin within Rubin /Williams
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to first pulmonary exacerbation, safety and efficacy in NCFB patients chronically infected with P. aeruginosa [48, 49]. Bayer has developed ciprofloxacin for dry powder inhalation (DPI) using PulmoSphereTM technology (Novartis) that is also being investigated for use in NCFB. Results for a phase II study show that twice-daily use for 28 days yields a statistically significant reduction in bacterial load [50]. As opposed to the ORBIT studies which limited their surveillance to P. aeruginosa, this study tracked all organisms and demonstrated efficacy against mucoid P. aeruginosa, S. pneumoniae, H. influenzae and M. catarrhalis (fig. 1). Two phase III studies, RESPIRE 1 and RESPIRE 2, are ongoing and will continue to investigate clinical efficacy and safety of ciprofloxacin DPI [51, 52]. In April 2014, this formulation was granted orphan drug designation for use in NCFB by the Food and Drug Administration in the USA [53].
S. aureus
0
H. influenzae
1
P. aeruginosa (nonmucoid)
pathogens at baseline and at end of treatment. Only results from valid cultures were considered. Cultures were excluded if subjects were administered concomitant antibacterials, if there were >25 squamous epithelial cells in the absence of P. aeruginosa or if there were ≤25 leukocytes for P. aeruginosa-negative cultures pretherapy. Reproduced with the permission of the European Respiratory Society [50]. EOT = End of treatment.
p = 0.438
4
P. aeruginosa (mucoid)
Fig. 1. Mean colony count of selected
p = 0.093
p = 0.880
5
Total bacterial load
Bacterial load (log10 CFU/g)
6
Table 1. Reported development of resistance after use of aerosolized antibiotics in NCFB N (n)a
Drug
Study type
Population
Colistin
prospective
NCFB and COPD
Colistin Gentamicin Tobramycin
R, PC R, PC DB, PC, crossover
NCFB with PA NCFB NCFB with PA
144 (73) 65 (27) 20 (20)
Tobramycin
OL
NCFB with PA
31 (31)
none none 10%b (to drug, to placebo) 6%
Ciprofloxacin (DRCFI)
phase II DB, R, PC
NCFB with PA
37 (18)
none
Ciprofloxacin (DPI)
phase II DB, R, PC
NCFB with positive 124 (60) culture
10%b
18 (18)
Resistance
Duration
Reference, first author
none
once daily for an average of 41 months twice daily for up to 6 months twice daily for 12 months twice daily for 6 months
[44] Steinfort, 2007
twice daily 14 days on/off for 12 weeks once daily 28 days on/off for 24 weeks twice daily for 28 days
[41] Scheinberg, 2005
[20] Haworth, 2014 [46] Murray, 2011 [39] Drobnic, 2004
[17] Serisier, 2013 [50] Wilson, 2013
DB = Double-blind; DRCFI = dual-release ciprofloxacin for inhalation; OL = open-label; PA = P. aeruginosa; PC = placebo-controlled; R = randomized. a Number of patients who completed the study (number on the drug). b Resistance lost after stopping therapy
a liposome, can increase antibiotic efficacy against common respiratory pathogens [57]. This formulation is able to penetrate CF sputum [58] and has shown antibiotic effectiveness at lower concentrations with improved targeting [59]. In addition to biofilm effects, there is also an interruption of quorum sensing, signaling molecule production and a decreased secretion of virulence factors [60]. In vitro investigations with gallium using CF sputum have identified a disruption of iron metabolism that prevents biofilm production and retards the growth of P. aeruginosa [61]. A liposomal formulation of gallium and gentamicin has also shown greater antibiotic efficacy than the use of gentamicin alone against P. aeruginosa growing in a biofilm in CF sputum [62]. Liposomal formulations are attractive in NCFB because they can be effectively aerosolized. They also offer the advantage of reducing the cytotoxicity of the encapsulated products by improving delivery, which allows reduced dosing [58, 62, 63]. Dosing reduction is also facilitated by surface modification of the lysosomes, i.e. PEGylation, which helps avoid immune system recognition and delays clearance [64]. Combination antibiotic therapy is also an area of active investigation, possessing the advantages of a broadened spectrum of activity, an improved efficiency of administration and synergistic antimicrobial effects which allow for reduced dosing. A combination of fosfomycin and tobramycin has shown efficacy in vitro against respiratory pathogens common in CF and NCFB [65, 66] and has been administered as an aerosol to adults with CF in early clinical trials [67]. This combination has also demonstrated synergistic bactericidal effects and eradicated P.
aeruginosa biofilms in vitro [68]. Aerosol delivery of a combination of amikacin and fosfomycin has been shown to achieve adequate drug concentrations in intubated patients with ventilator-associated pneumonia without adverse effects, although the clinical response here was not actually reported [69]. There has also been a demonstration of synergy with a combination of colistin and tobramycin in vitro, in a rat model and in an early clinical trial with CF patients [70].
Aerosolized Antibiotics for NCFB
Respiration 2014;88:177–184 DOI: 10.1159/000366000
Emergence of Bacterial Resistance
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With aerosol delivery, antibiotic concentrations in the proximal airway can greatly exceed those obtained safely by other means [71]. There is an advantage to delivering antibiotics that have greater efficacy at higher AUC/MIC ratios, as this can help to overcome efflux pump-driven bacterial resistance [33, 71]. Unfortunately, aerosol delivery to the lung is not uniform, and this has the potential to create antibiotic concentration gradients, i.e. much lower concentrations are found in deeper parts of the lung [33]. Continued subtherapeutic exposure allows bacterial adaptation and fosters the development of resistance [72]. It is now recognized that most of the bacteria associated with chronic infection in CF, NCFB and other conditions are capable of biofilm formation. In addition to providing barrier protection against antibiotics, this also establishes a sustained, protected environment that allows for lateral gene exchange and increases the likelihood of organisms acquiring more resistance [73].
Table 2. Active clinical trials, as of June 2014, studying aerosolized antibiotics for use in NCFB
Study
Phase
Identifier
Status
Pulmaquin in NCFB (ORBIT-4)
III
NCT02104245
Not yet recruiting
Dual-release ciprofloxacin for inhalation in NCFB (ORBIT-3)
III
NCT01515007
Recruiting
Ciprofloxacin DPI in NCFB (RESPIRE 1)
III
NCT01764841
Recruiting
Ciprofloxacin DPI in NCFB (RESPIRE 2)
III
NCT02106832
Recruiting
Combined administration of nebulized amikacin in patients with acute exacerbation of NCFB
III
NCT02081963
Ongoing but not recruiting
Efficacy and tolerability of the tobramycin podhaler in bronchiectasis patients with chronic P. aeruginosa infection (TOBI)
N/S
NCT02102152
Not yet recruiting
Pharmacokinetic evaluation and tolerability of dry powder tobramycin by a novel device in patients with NCFB
I, II
NCT02035488
Recruiting
Source: ClinicalTrials.gov. N/S = Not specified.
References
Discussion
Increasing recognition of the prevalence and burden of NCFB has spurred research into its epidemiology, pathogenesis and management. It is clear, despite the variety of causes, that NCFB is sufficiently distinct in many ways from CF, and that a default approach of using therapies proven in CF is not adequate and is even potential182
ly counterproductive. Antibiotic therapy for acute and chronic infections has shown variable results. Treatment clearly reduces bacterial load as well as symptoms like cough and sputum expectoration to the point that improvements in the quality of life of patients have been demonstrated. Preferred antibiotics and routes of delivery for management have not been established. There is growing interest in pursuing aerosol delivery because of its convenience and lower side-effect profiles, although admittedly, this has been biased due to the demonstrated successes with CF. Technological advancements in aerosolization and drug development have enabled investigation of novel therapies and the initial results are promising, with different formulations of ciprofloxacin and amikacin entering phase III trials. Alternative formulations of inhaled tobramycin, which may prove to be better-tolerated, are at the stage of early clinical trials (table 2). It is too early to speculate on the efficacy and cost benefits of therapy.
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1 Goeminne P, Dupont L: Non-cystic fibrosis bronchiectasis: diagnosis and management in 21st century. Postgrad Med J 2010; 86: 493– 501. 2 Cohen M, Sahn SA: Bronchiectasis in systemic diseases. Chest 1999;116:1063–1074. 3 Pasteur MC, Helliwell SM, Houghton SJ, Webb SC, Foweraker JE, Coulden RA, et al: An investigation into causative factors in patients with bronchiectasis. Am J Respir Crit Care Med 2000;162:1277–1284.
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There is a growing understanding of the microenvironment within the CF lung, and particularly its role in the development of antibiotic resistance. In CF treatment, there have been limited reports of acquired resistance to tobramycin [74], but this is usually sustained for only a few months after stopping therapy [34]. There have also been reports of acquired resistance to aztreonam when used twice daily, but not when used 3 times a day [75]. Acquired resistance to colistin is rare [76]. While investigations to date have not identified a clinically relevant resistance to inhaled antibiotics in CF [77], concerns remain that continued and more widespread use will increase the risk of developing resistance [10]. There are known differences in antibiotic activity between the CF and non-CF lung, particularly with aminoglycosides and fluoroquinolones [71, 78], and this may change adaptation pressure. Outcomes in NCFB, however, appear similar to those in CF, including a likely loss of resistance after stopping therapy [50]. Our results are summarized in table 1.
Aerosolized Antibiotics for NCFB
18 Kapur N, Masters IB, Morris PS, Galligan J, Ware R, Chang AB: Defining pulmonary exacerbation in children with non-cystic fibrosis bronchiectasis. Pediatr Pulmonol 2012;47: 68–75. 19 Cole PJ: Inflammation: a two-edged sword – the model of bronchiectasis. Eur J Respir Dis Suppl 1986;147:6–15. 20 Haworth CS, Foweraker JE, Wilkinson P, Kenyon RF, Bilton D: Inhaled colistin in patients with bronchiectasis and chronic Pseudomonas aeruginosa infection. Am J Respir Crit Care Med 2014;189:975–982. 21 Angrill J, Agustí C, de Celis R, Filella X, Rañó A, Elena M, et al: Bronchial inflammation and colonization in patients with clinically stable bronchiectasis. Am J Respir Crit Care Med 2001;164:1628–1632. 22 Kapur N, Grimwood K, Masters IB, Morris PS, Chang AB: Lower airway microbiology and cellularity in children with newly diagnosed non-CF bronchiectasis. Pediatr Pulmonol 2012;47:300–307. 23 Chang AB, Bilton D: Exacerbations in cystic fibrosis. 4. Non-cystic fibrosis bronchiectasis. Thorax 2008;63:269–276. 24 Rogers GB, van der Gast CJ, Cuthbertson L, Thomson SK, Bruce KD, Martin ML, et al: Clinical measures of disease in adult non-CF bronchiectasis correlate with airway microbiota composition. Thorax 2013;68:731–737. 25 Seitz AE, Olivier KN, Steiner CA, Montes de Oca R, Holland SM, Prevots DR: Trends and burden of bronchiectasis-associated hospitalizations in the United States, 1993–2006. Chest 2010;138:944–949. 26 Rubin BK: Did Lady Windermere have cystic fibrosis? Chest 2006;130:937–938. 27 Sexton P, Harrison AC: Susceptibility to nontuberculous mycobacterial lung disease. Eur Respir J 2008;31:1322–1333. 28 Rademacher J, Welte T: Bronchiectasis – diagnosis and treatment. Dtsch Ärztebl Int 2011;108:809–815. 29 Martínez-García MÁ, Soler Cataluña JJ, Perpiñá-Tordera M, Román-Sánchez P, Soriano J: Factors associated with lung function decline in adult patients with stable non-cystic fibrosis bronchiectasis. Chest 2007;132:1565– 1572. 30 King PT, Holdsworth SR, Freezer NJ, Villanueva E, Holmes PW: Microbiologic followup study in adult bronchiectasis. Respir Med 2007;101:1633–1638. 31 Wong C, Jayaram L, Karalus N, Eaton T, Tong C, Hockey H, et al: Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet 2012;380:660–667. 32 Evans DJ, Greenstone M: Long-term antibiotics in the management of non-CF bronchiectasis – do they improve outcome? Respir Med 2003;97:851–858. 33 Rubin BK: Aerosolized antibiotics for noncystic fibrosis bronchiectasis. J Aerosol Med Pulm D 2008;21:71–76.
34 Martínez-García MÁ, Máiz Carro L, CatalánSerra P: Treatment of non-cystic fibrosis bronchiectasis. Archiv Bronconeumol 2011; 47:599–609. 35 Hanif SNM, Garcia-Contreras L: Pharmaceutical aerosols for the treatment and prevention of tuberculosis. Front Cell Infect Microbiol 2012;2:118. 36 Nikander K, Prince I, Coughlin S, Warren S, Taylor G: Mode of breathing – tidal or slow and deep – through the I-neb Adaptive Aerosol Delivery (AAD) System affects lung deposition of 99mTc-DTPA. J Aerosol Med Pulm D 2010;23:S-37–S-43. 37 Morosini MI, García-Castillo M, Loza E, Pérez-Vázquez M, Baquero F, Cantón R: Breakpoints for predicting Pseudomonas aeruginosa susceptibility to inhaled tobramycin in cystic fibrosis patients: use of high-range Etest strips. J Clin Microbiol 2005; 43: 4480– 4485. 38 Couch LA: Treatment with tobramycin solution for inhalation in bronchiectasis patients with Pseudomonas aeruginosa. Chest 2001; 120:114S–117S. 39 Drobnic ME: Inhaled tobramycin in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection with Pseudomonas aeruginosa. Ann Pharmacother 2004; 39: 39–44. 40 Bilton D, Henig N, Morrissey B, Gotfried M: Addition of inhaled tobramycin to ciprofloxacin for acute exacerbations of Pseudomonas aeruginosa infection in adult bronchiectasis. Chest 2006;130:1503–1510. 41 Scheinberg P, Shore E: A pilot study of the safety and efficacy of tobramycin solution for inhalation in patients with severe bronchiectasis. Chest 2005;127:1420–1426. 42 Barker A, O’Donnell A, Thompson P, et al: Two phase 3 placebo-controlled trials of aztreonam lysine for inhalation (AZLI) for noncystic fibrosis bronchiectasis (NCFB). Eur Respir J 2013;42(suppl 57):4136. 43 Michalopoulos A, Papadakis E: Inhaled antiinfective agents: emphasis on colistin. Infection 2010;38:81–88. 44 Steinfort DP, Steinfort C: Effect of long-term nebulized colistin on lung function and quality of life in patients with chronic bronchial sepsis. Intern Med J 2007;37:495–498. 45 Dhar R, Anwar GA, Bourke SC, Doherty L, Middleton P, Ward C, et al: Efficacy of nebulised colomycin in patients with non-cystic fibrosis bronchiectasis colonised with Pseudomonas aeruginosa. Thorax 2010; 65: 553– 553. 46 Murray MP, Govan JRW, Doherty CJ, Simpson AJ, Wilkinson TS, Chalmers JD, et al: A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2011; 183: 491– 499.
Respiration 2014;88:177–184 DOI: 10.1159/000366000
183
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4 Fuschillo S, De Felice A, Balzano G: Mucosal inflammation in idiopathic bronchiectasis: cellular and molecular mechanisms. Eur Respir J 2008;31:396–406. 5 De Soyza A, Brown JS, Loebinger MR; Bronchiectasis Research and Academic Network: Research priorities in bronchiectasis. Thorax 2013;68:695–696. 6 Short- and long-term antibiotic treatment reduces airway and systemic inflammation in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2012;186:657–665. 7 Metersky ML, O’Donnell AE: Nebulized colistin for non-cystic fibrosis bronchiectasis: déjà vu all over again? Am J Respir Crit Care Med 2014;189:1151–1152. 8 Wills PJ, Wodehouse T, Corkery K, Mallon K, Wilson R, Cole PJ: Short-term recombinant human DNase in bronchiectasis. Effect on clinical state and in vitro sputum transportability. Am J Respir Crit Care Med 1996;154: 413–417. 9 O’Donnell AE, Barker AF, Ilowite JS, Fick RB: Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase I. rhDNase Study Group. Chest 1998;113:1329– 1334. 10 Serisier DJ: The evidence base for non-CF bronchiectasis is finally evolving. Respirology 2014;19:295–297. 11 Barker AF, Couch L, Fiel SB, Gotfried MH, Ilowite J, Meyer KC, et al: Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis. Am J Respir Crit Care Med 2000; 162: 481– 485. 12 Feldman C: Bronchiectasis: new approaches to diagnosis and management. Clin Chest Med 2011;32:535–546. 13 McShane PJ, Naureckas ET, Tino G, Strek ME: Non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2013;188:647–656. 14 Amorim A, Gamboa F, Azevedo P: New advances in the therapy of non-cystic fibrosis bronchiectasis. Rev Port Pneumol 2013; 19: 266–275. 15 Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al: Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med 1994;331:637–642. 16 Vendrell M, de Gracia J, Olveira C, Martínez MA, Girón R, Máiz L, et al: Diagnosis and treatment of bronchiectasis. Spanish Society of Pneumology and Thoracic Surgery. Arch Bronconeumol 2008;44:629–640. 17 Serisier DJ, Bilton D, De Soyza A, Thompson PJ, Kolbe J, Greville HW, et al: Inhaled, dualrelease liposomal ciprofloxacin in non-cystic fibrosis bronchiectasis (ORBIT-2): a randomised, double-blind, placebo-controlled trial. Thorax 2013;68:812–817.
184
58 Halwani M, Hebert S, Suntres ZE, Lafrenie RM, Azghani AO, Omri A: Bismuth-thiol incorporation enhances biological activities of liposomal tobramycin against bacterial biofilm and quorum-sensing molecules production by Pseudomonas aeruginosa. Int J Pharmaceut 2009;373:141–146. 59 Alipour M, Suntres ZE, Lafrenie RM, Omri A: Attenuation of Pseudomonas aeruginosa virulence factors and biofilms by co-encapsulation of bismuth-ethanedithiol with tobramycin in liposomes. J Antimicrob Chemother 2010;65:684–693. 60 Alhariri M, Omri A: Efficacy of liposomal bismuth-ethanedithiol-loaded tobramycin after intratracheal administration in rats with pulmonary Pseudomonas aeruginosa infection. Antimicrob Agents Chemother 2013;57:569– 578. 61 Kaneko Y, Thoendel M, Olakanmi O, Britigan BE, Singh PK: The transition metal gallium disrupts Pseudomonas aeruginosa iron metabolism and has antimicrobial and antibiofilm activity. J Clin Invest 2007;117:877–888. 62 Halwani M, Yebio B, Suntres ZE, Alipour M, Azghani AO, Omri A: Co-encapsulation of gallium with gentamicin in liposomes enhances antimicrobial activity of gentamicin against Pseudomonas aeruginosa. J Antimicrob Chemother 2008;62:1291–1297. 63 Alhajlan M, Alhariri M, Omri A: Efficacy and safety of liposomal clarithromycin and its effect on Pseudomonas aeruginosa virulence factors. Antimicrob Agents Chemother 2013; 57:2694–2704. 64 Chono S, Suzuki H, Togami K, Morimoto K: Efficient drug delivery to lung epithelial lining fluid by aerosolization of ciprofloxacin incorporated into PEGylated liposomes for treatment of respiratory infections. Drug Dev Ind Pharm 2011;37:367–372. 65 MacLeod DL, Barker LM, Sutherland JL, Moss SC, Gurgel JL, Kenney TF, et al: Antibacterial activities of a fosfomycin/tobramycin combination: a novel inhaled antibiotic for bronchiectasis. J Antimicrob Chemother 2009;64:829–836. 66 McCaughey G, McKevitt M, Elborn JS, Tunney MM: Antimicrobial activity of fosfomycin and tobramycin in combination against cystic fibrosis pathogens under aerobic and anaerobic conditions. J Cyst Fibros 2012; 11: 163–172. 67 Trapnell BC, McColley SA, Kissner DG, Rolfe MW, Rosen JM, McKevitt M, et al: Fosfomycin/tobramycin for inhalation in patients with cystic fibrosis with Pseudomonas airway infection. Am J Respir Crit Care Med 2012;185: 171–178.
Respiration 2014;88:177–184 DOI: 10.1159/000366000
68 Anderson GG, Kenney TF, MacLeod DL, Henig NR, O’Toole GA: Eradication of Pseudomonas aeruginosa biofilms on cultured airway cells by a fosfomycin/tobramycin antibiotic combination. Pathog Dis 2013;67:39–45. 69 Montgomery AB, Vallance S, Abuan T, Tservistas M, Davies A: A Randomized doubleblind placebo-controlled dose-escalation phase 1 study of aerosolized amikacin and fosfomycin delivered via the PARI Investigational eFlow® Inline Nebulizer System in mechanically ventilated patients. J Aerosol Med Pulm Drug Deliv 2014;27:1–8. 70 Herrmann G, Yang L, Wu H, Song Z, Wang H, Høiby N, et al: Colistin-tobramycin combinations are superior to monotherapy concerning the killing of biofilm Pseudomonas aeruginosa. J Infect Dis 2010;202:1585–1592. 71 Dudley MN, Loutit J, Griffith DC: Aerosol antibiotics: considerations in pharmacological and clinical evaluation. Curr Opin Biotechnol 2008;19:637–643. 72 Falagas ME, Bliziotis IA, Kasiakou SK, Samonis G, Athanassopoulou P, Michalopoulos A: Outcome of infections due to pandrug-resistant (PDR) Gram-negative bacteria. BMC Infect Dis 2005;5:24. 73 Delissalde F, Amábile-Cuevas CF: Comparison of antibiotic susceptibility and plasmid content, between biofilm producing and nonproducing clinical isolates of Pseudomonas aeruginosa. Int J Antimicrob Agents 2004;24: 405–408. 74 Ryan G, Singh M, Dwan K: Inhaled antibiotics for long-term therapy in cystic fibrosis (review). Cochrane Database Syst Rev 2011; CD001021. 75 Oermann CM, McCoy KS, Retsch-Bogart GZ, Gibson RL, McKevitt M, Montgomery AB: Pseudomonas aeruginosa antibiotic susceptibility during long-term use of aztreonam for inhalation solution (AZLI). J Antimicrob Chemother 2011;66:2398–2404. 76 Conway DSP, Brownlee KG, Denton M, Peckham DG: Antibiotic treatment of multidrug-resistant organisms in cystic fibrosis. Am J Respir Med 2003;2:321–332. 77 Conway DS: Nebulized antibiotic therapy: the evidence. Chron Respir Dis 2005;2:35–41. 78 Hunt BE, Weber A, Berger A, Ramsey B, Smith AL: Macromolecular mechanisms of sputum inhibition of tobramycin activity. Antimicrob Agents Chemother 1995; 39: 34– 39.
Rubin /Williams
Downloaded by: Kainan University 203.64.11.45 - 3/9/2015 10:27:07 PM
47 Pecota N: Aradigm reports successful ORBIT1 bronchiectasis study with inhaled liposomal ciprofloxacin. http://investor.aradigm.com/ releasedetail.cfm (accessed 17 May 2014). 48 Aradigm Corporation, Grifols Therapeutics Inc: Phase 3 study with dual-release ciprofloxacin for inhalation in non-CF bronchiectasis. http://clinicaltrials.gov/ct2/show/study/ NCT01515007 (accessed 26 May 2014). 49 Aradigm Corporation, Grifols Therapeutics Inc: Phase 3 study with pulmaquin in non-CF bronchiectasis (ORBIT-4). http://clinicaltrials.gov/ct2/show/study/NCT02104245 (accessed 26 May 2014). 50 Wilson R, Welte T, Polverino E, De Soyza A, Greville H, O’Donnell A, et al: Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis: a phase II randomised study. Eur Respir J 2013;41:1107–1115. 51 Bayer, Novartis: Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis (non-CF BE) (RESPIRE 1). http://clinicaltrials.gov/ct2/show/NCT01764841 (accessed 17 May 2014). 52 Bayer, Novartis: Ciprofloxacin dry powder for inhalation (DPI) in non-cystic fibrosis bronchiectasis (non-CF BE) (RESPIRE 2). http://clinicaltrials.gov/ct2/show/NCT02106 832?term=NCT02106832&rank=1 (accessed 17 May 2014). 53 Bayer: FDA grants orphan drug designation for Bayer’s investigational ciprofloxacin DPI (dry powder for inhalation) for treatment of non-cystic fibrosis bronchiectasis. Bayer Healthcare 2014, http://www.pharma.bayer. com/html/pdf/Final-FDA_Grants_Orphan_ Drug_Designation_for_Investigational_Ciprofloxacin_DPI.pdf. 54 Manzanedo D, Brande M, Kramer S, et al: Formulation characterization of a novel levofloxacin pulmonary dry powder drug delivery technology. Respiratory Drug Delivery Conference, Phoenix, 2012, pp 1–4. 55 Qilu Hospital: Combined administration of nebulized amikacin in patients with acute exacerbation of non-cystic fibrosis bronchiectasis. http://clinicaltrials.gov/ct2/show/study/ NCT02081963 (accessed 17 May 2014). 56 Huang CT, Stewart PS: Reduction of polysaccharide production in Pseudomonas aeruginosa biofilms by bismuth dimercaprol (BisBAL) treatment. J Antimicrob Chemother 1999;44:601–605. 57 Halwani M, Blomme S, Suntres ZE, Alipour M, Azghani AO, Kumar A, et al: Liposomal bismuth-ethanedithiol formulation enhances antimicrobial activity of tobramycin. Int J Pharmaceut 2008;358:278–284.
