Inhaled versus nebulised tobramycin: A real world comparison in adult cystic fibrosis (CF)

JCF-01045; No of Pages 6

Journal of Cystic Fibrosis xx (2014) xxx – xxx www.elsevier.com/locate/jcf

Original Article

Inhaled versus nebulised tobramycin: A real world comparison in adult cystic fibrosis (CF)☆ M.J. Harrison a,b , M. McCarthy a , C. Fleming a , C. Hickey a , C. Shortt a , J.A. Eustace b , D.M. Murphy a,b , B.J. Plant a,b,⁎ a

Cork Adult Cystic Fibrosis Centre, University College Cork, Cork University Hospital, Wilton, Cork, Ireland b HRB Clinical Research Facility, University College Cork, Cork, Ireland Received 30 January 2014; revised 9 April 2014; accepted 9 April 2014

Abstract Background: There are no published data on real-life clinical experience comparing inhaled antibiotic therapy via new rapid delivery systems with nebulised antibiotic therapy in CF. This real world study compares safety, effectiveness and tolerability using tobramycin inhaled powder (TIP) versus tobramycin inhaled solution (TIS). Methods: Adult patients with CF commencing TIP (n = 78) completed a questionnaire assessing safety, efficacy, tolerability, patient-satisfaction and self-reported adherence to TIS at baseline and during 12 months of TIP therapy. FEV1% predicted and exacerbation rate were recorded at each visit. Results: There was a significant improvement in adherence scores, with a significant decrease in the number of intravenous antibiotic courses received during 12 months of TIP compared with the preceding 12 months using TIS. 94% of patients who had previously used TIS preferred TIP therapy over TIS. Conclusions: Inhaled powder tobramycin in CF is associated with improved adherence, tolerability and decreased exacerbation rates compared to nebulised treatment in real-life practice. © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

1. Introduction Progressive respiratory failure due to recurrent respiratory tract infection caused by Pseudomonas aeruginosa is the most common cause of morbidity and mortality in people with CF [1–3]. Advances in therapy over the last 20 years have resulted in dramatic improvements in median survival [4,5], but also in a significant increase in the treatment burden of people with CF. The development of nebulised anti-pseudomonal antibiotic therapy represents one of the most important advances and ☆ Data from this study was presented as a poster presentation at the ECFS 2013, Lisbon, June 2013(1). ⁎ Corresponding author at: Cork Adult Cystic Fibrosis Centre, University College Cork, Cork University Hospital, Wilton, Cork, Ireland. Tel.: + 353 214922327; fax: + 353 214920168. E-mail address: [email protected] (B.J. Plant).

is an important therapeutic option for people with CF who are chronically infected with P. aeruginosa [6] resulting in improved quality of life [7], improved lung function [8], decreased hospitalisations [9], and decreased mortality [10]. However, this twice-daily regimen constitutes a significant portion of the CF patient's treatment burden as administration time is approximately 15 min per dose excluding time for cleaning and disinfection of the delivery device (approximately 20 min per use) [11]. In adults with CF, perceived treatment burden is highly associated with the number of nebulised medications prescribed [12]. High treatment burden has been demonstrated in children [13] and adults [12] with CF—adult subjects reported spending an average of 108 min (SD ± 58 min) on daily CF treatments—and is associated with a reduction in adherence with therapies, particularly in adolescents and adults trying to balance family, work, education, and other responsibilities with the management of their disease

http://dx.doi.org/10.1016/j.jcf.2014.04.004 1569-1993/© 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Please cite this article as: Harrison MJ, et al, Inhaled versus nebulised tobramycin: A real world comparison in adult cystic fibrosis (CF), J Cyst Fibros (2014), http:// dx.doi.org/10.1016/j.jcf.2014.04.004

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[12]. Reduced adherence to therapies has been identified as the single most important cause of treatment failure [14]. Rates of adherence vary depending on the intensity and complexity of the prescribed treatment and on the measure of adherence used. Adherence rates for all therapies amongst CF [15] and non-CF [16] paediatric patients have been reported to be below 50%, while adherence rates for all therapies amongst adults with CF have been reported at 65% [17]. Adherence to nebuliser therapy has been reported as 65–80% via self-reporting, 50–60% via clinician reporting, and 36% via electronic download [18,19]. With the number of treatment options available to people with CF likely to increase, it is imperative that new therapies are designed with a view to minimizing or reducing their impact on treatment burden and, therefore, potential impact on adherence. A recent Phase III clinical trial [20] comparing a novel inhaled powder antibiotic delivery system (tobramycin inhaled powder, TIP) to the established inhaled solution (or nebulised) delivery system (tobramycin inhaled solution, TIS) demonstrated similar efficacy and safety profiles for both methods over a 6-month study period with a significantly reduced administration time for the inhaled powder delivery system (mean: 5.6 versus 19.7 min).Treatment satisfaction was significantly higher for the inhaled powder delivery system with regard to perceived effectiveness, convenience, and global satisfaction. However, the rate of cough suspected to be study drug related was higher in TIP-treated patients (TIP: 25.3%; TIS: 4.3%), as was the overall discontinuation rate (TIP: 26.9%; TIS: 18.2%). Another clinical trial showed non-inferiority and increased patient satisfaction with a different dry powder inhaler compared to traditional nebulised therapy in adults with CF [21]. An observational study comparing delivery of tobramycin inhaled solution (TIS) via a more rapid E-Flow delivery system and a traditional, slower delivery system showed no difference in lung function, with decreased treatment burden and increased patient satisfaction using the more rapid system [22]. To date, there is no published data on real-life experience comparing TIP therapy with TIS therapy in CF. We hypothesise that use of a rapid inhaled powder antibiotic delivery system in a real world clinical setting will reduce treatment burden and increase adherence in adult patients with CF. In a prospective study we document safety, effectiveness, adherence and tolerability in a cohort of CF adults receiving tobramycin inhaled powder (TIP) 112 mg twice daily and compare this with tobramycin inhaled solution (TIS) 300 mg twice daily.

2. Methods 2.1. Subjects Adult CF patients attending the Cork Adult CF Centre commencing TIP were recruited from November 2011 and prospectively analysed up to April 2013. All participants 16 years or greater (as per guidelines for transition at our centre) who were chronically infected with P. aeruginosa as per the Leeds criteria [23] were offered TIP therapy, as part of “best practice” clinical care based on the clinical trial data showing

similar efficacy and safety profiles, reduced administration time and higher treatment satisfaction with TIP compared to TIS.

2.2. Study design At baseline visit, retrospective review of all participants' medical notes over a 12-month period was performed to assess previous use of TIS, exacerbation rate (measured by the number of intravenous antibiotic courses received), along with gender, age, and genotype. A supervised trial dose of TIP therapy was administered in the CF Centre with spirometry pre- (baseline) and post- the trial dose using the CareFusion MicroLab™ Spirometer, which is regularly calibrated. If a patient presented for a routine visit while experiencing an infective exacerbation, standard treatments for an infective exacerbation were instituted, with the patient asked to return after 2 weeks of treatment for re-assessment, where possible. If the patient had returned to their baseline symptomatically at the return visit, questionnaire and spirometry were performed and these values were used as the value for the index visit. Patients were reminded at each interview to give their answers to the questionnaire based on their symptoms over the whole 3-month period and not just the most recent period preceding the visit, particularly if this period included an infective exacerbation. Participants who experienced symptoms of bronchospasm or demonstrated ≥ 10% drop in the % predicted FEV1 received 400 μg of salbutamol via a large volume spacer and spirometry was repeated after 15 min to examine for reversibility. Participants who did not experience resolution of their symptoms or demonstrate reversibility post-bronchodilator were excluded and did not commence TIP therapy.

2.3. Patient assessment All participants completed a questionnaire (a modified version of the questionnaire used in the phase III clinical trial [20]) assessing safety, effectiveness, tolerability, patient satisfaction and self-reported adherence to TIS at baseline visit, and at 3, 6, 9 and 12 months of TIP therapy. Participants were asked to record their cough as no cough (score = 0), mild (score = 1), moderate (score = 2) or severe (score = 3) and a cough score was recorded at all time points. Adherence was recorded as excellent (N 80% adherence to therapy, score = 3), moderate (50–80% adherence to therapy, score = 2), or poor (b 50% adherence to therapy, score = 1) by patient self-reporting using a modified version of a previously described self-report adherence assessment tool [19]. FEV1% predicted and exacerbation rate—measured by the number of intravenous antibiotic courses received since previous visit—was recorded at each time-point. If a change of intravenous antibiotics was deemed clinically necessary, this was counted as a separate course of antibiotics. Study visits were included if they occurred at a time point +/− 4 weeks from the scheduled visit. If a visit occurred outside of this time point and not within 4 weeks of another time point, it was considered a missed visit.

Please cite this article as: Harrison MJ, et al, Inhaled versus nebulised tobramycin: A real world comparison in adult cystic fibrosis (CF), J Cyst Fibros (2014), http:// dx.doi.org/10.1016/j.jcf.2014.04.004

M.J. Harrison et al. / Journal of Cystic Fibrosis xx (2014) xxx–xxx

2.4. Statistical considerations Chi-square, Mann–Whitney U and Wilcoxon signed rank testing were used to compare self-reported adherence and cough scores, exacerbation rates, (calculated as the number of courses of intravenous antibiotics) and FEV1% predicted between participants taking TIS therapy (12-month retrospective data) to those who completed 12-months of TIP therapy (12-month prospective data). 2.5. Ethical approval As this real world monitoring measured the response to changes in standard clinical practice prospectively and routinely in CF clinics, an ethics waiver was granted by the Clinical Research Ethics Committee of the Cork Teaching Hospitals. 3. Results 3.1. Demographics All eligible patients who attended the Cork Adult Cystic Fibrosis Centre during the study period were offered TIP therapy. A total of 78 patients were recruited (see Table 1 and Fig. 1). 51/78 (65%) of these were using TIS at time of recruitment. Prospective 6-month, 9-month and 12-month data was obtained for 39, 31 and 40 patients respectively (see Fig. 1). The missing data at 6-, 9-, and 12 months relates to missed collection of data due to patient non-attendance at routine clinic visit. One patient died during the observation period. This death occurred in a Table 1 Baseline patient demographics of patients at baseline. Variable

n = 78

Median age in years (range) Male gender Median FEV1% predicted (IQR) Genotype: Class I–III mutation Use of TIS at baseline Self-reported cough score of TIS users (n = 51) 0 1 2 3 Self-reported adherence score of TIS users (n = 49) 1 2 3 No. of IVAB courses received in previous 12 months using TIS (n = 50) 0 courses 1 course 2 courses ≥3 courses No. of IVAB courses received in previous 12 months in patients not using TIS (n = 50) 0 courses 1 course 2 courses ≥3 courses

26.3 (16–56) 46 (59%) 63.5 (45.5–74) 73 (94%) 51 (65%) 19 28 2 2 12 15 22

22 10 7 11

14 7 1 3

3

patient with advanced CF lung disease and was deemed to be unrelated to TIP therapy. One patient received a lung transplant, and 3 were lost to follow up, leaving a total of 73 patients. 3.2. Safety All patients tolerated a supervised trial of TIP therapy. No patient demonstrated N 10% reduction in FEV1% predicted post-inhalation. 1 patient showed a 9% reduction in FEV1 during his trial of TIP therapy but did not report symptoms suggestive of bronchospasm. This patient received 400 mcg of inhaled salbutamol via spacer device with return of FEV1% predicted to baseline value and has subsequently tolerated TIP therapy over 6 months. 3.3. Tolerability 10/73 (14%) discontinued TIP over a 6 month period, with all participants discontinuing TIP therapy within one month of commencement. Of these, 9/10 discontinued due to bronchospasm or cough, while 1/10 discontinued due to haemoptysis (this patient stopped all inhaled therapies after one month of TIP). 4/10 were previously intolerant of TIS due to bronchospasm or cough. 4/10 had tolerated TIS previously and successfully recommenced TIS. 2/10 were commenced on TIS de novo after discontinuing TIP. There was no significant difference seen in reported cough scores in participants at baseline (n = 51), 6 months (n = 39), 9 months (n = 31) and 12 months (n = 40) (p = 0.408). In a paired subgroup analysis (n = 28) of patients who previously used TIS comparing cough score at baseline versus cough score at 12 months there was no significant difference in reported cough between patients at baseline in the TIS group and repeated measures in the same patients in the TIP group at 12 months (p = 0.617). 2/78 patients reported previous dysphonia on TIS with 1 patient reporting transient self-limiting dysphonia in the TIP group. 1/78 patients reported previous dysguesia on TIS with 2 patients reporting transient self-limiting dysguesia in the TIP group. 2 patients developed oral candidiasis, which responded to standard anti-fungal treatment and improved oral hygiene. 49/51 (96%) patients who were using TIS at study entry preferred TIP at all recorded time points citing “time-saving” and “convenience” compared to TIS as the most common reasons. Both patients who stated a preference for TIS at 12 months had preferred TIP at 6 months (no 9-month data was available for either patient). 3.4. Effectiveness 3.4.1. Adherence There was a significant improvement in adherence scores at baseline on TIS compared to adherence scores at 3 months, 6 months, 9 months and 12 months using TIP (p = 0.002). Fig. 2 shows the adherence scores reported at each time point for all patient visits. The proportion of subjects reporting excellent adherence was higher across all time points using TIP

Please cite this article as: Harrison MJ, et al, Inhaled versus nebulised tobramycin: A real world comparison in adult cystic fibrosis (CF), J Cyst Fibros (2014), http:// dx.doi.org/10.1016/j.jcf.2014.04.004

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M.J. Harrison et al. / Journal of Cystic Fibrosis xx (2014) xxx–xxx

Fig. 1. Flow diagram of tobramycin inhaled powder use.

versus the proportion reporting excellent adherence using TIS at study entry. 1 patient reported taking TIP once daily instead of twice daily. This patient's data was included in the study and was recorded as “poor” (b 50%) adherence according to the questionnaire criterion regarding adherence. Subgroup analysis was performed after the first 40 patients completed 12 months of TIP therapy. 28 of the 40 patients who completed 12 months of TIP were using TIS at study entry. 33/40 (83%) reported excellent adherence to TIP at 12 months. 12/28 (43%) who were using TIS at baseline reported excellent adherence to TIS. In a paired subgroup analysis (n = 28) comparing adherence scores at baseline to adherence scores at 12 months there was a significantly improved self-reported adherence score in patients who completed 12 months of TIP

100% 90% 80%

3.4.2. Intravenous antibiotic use There was a statistically significant decrease in the number of intravenous antibiotic courses received in participants after 12 months of TIP (median 0 {IQR 0–1}) compared with the number of courses of intravenous antibiotics received by the same participants during the preceding 12 months (median 0 {IQR 0–1}) (n = 40) (p b 0.001). Paired analysis in a subgroup using TIS at baseline (median 0.5, {IQR 0–1.75}) who completed 12-month follow-up on TIP (n = 28) (median 0, {IQR 0–1.0}) showed a statistically significant reduction in

22

70%

100%

60%

33

31

29 28

90%

5

5 6

80%

50% 40%

when compared with adherence scores in the same patients at baseline using TIS (Z score = − 2.95, p = 0.003). Fig. 3 shows the change from baseline adherence at 6 months, 9 months, and 12 months in participants with paired data at these time points. 41% (n = 29) participants reported an improvement in adherence at 6 months, while 50% reported an improvement in adherence score at 9-months (n = 11) and 12 months (n = 14).

70%

7 9 5

60%

15

50% 30%

40% 30%

20% 10%

12

5

7

7 3

3

0%

1

1

2=moderate

9

13

20% 10%

2

TIS at baseline TIP at 3 months TIP at 6 months TIP at 9 months TIPat 12 months (n=49) (n=41) (n=37) (n=32) (n=40) 3=excellent

16

0%

2

1

6 months (n=29)

1

9 months (n=22)

+2

+1

0

12 months (n=28)

1

1=poor

Fig. 2. Self-reported adherence score for all patient visits.

Fig. 3. Change from baseline adherence score in patients with longitudinal data at 6, 9, and 12 months.

Please cite this article as: Harrison MJ, et al, Inhaled versus nebulised tobramycin: A real world comparison in adult cystic fibrosis (CF), J Cyst Fibros (2014), http:// dx.doi.org/10.1016/j.jcf.2014.04.004

M.J. Harrison et al. / Journal of Cystic Fibrosis xx (2014) xxx–xxx 30 TIS 22

5

while 4/9 (45%) discontinued TIP within 2 weeks secondary to cough.

TIP

4. Discussion

11

10 7 5

3 1

0 courses

1 course

2 courses

p=0.000

p=0.609

p=0.03

p=0.000

Fig. 4. Number of intravenous antibiotic courses received in 12 months retrospectively during TIS vs. 12 months prospectively during TIP.

intravenous antibiotic use in this group over 12 months of TIP therapy (p = 0.003). 75% (n = 30) of participants required no intravenous antibiotics prospectively during 12 months of TIP compared with 44% (n = 22) of participants in the preceding 12 months retrospectively on TIS (p b 0.001) (see Fig. 4). 27 patients were TIS-naïve on study entry. Retrospective analysis showed that in the year prior to study entry, 14/27 patients in the TIS-naive group required no IVABs, 7 patients required 1 course, 1 patient required 2 courses and 3 patients required ≥ 3 courses. 2 patients had no recorded data. 10/27 study participants had paired data showing IVAB requirements prospectively during 12 months of TIP therapy. In these 10 patients, 9 patients required no IVABS and 1 patient required 3 courses of IVABs. 4 of the 10 patients who had paired data available showed a reduction in the number of courses of IVABs required during 12 months of TIP, and the other 6 patients required the same number of courses in both periods. 3.4.3. Lung function Lung function was stable at all time points with no significant difference between FEV1% predicted at baseline (median 63.5 {IQR 45.5–74}) compared with FEV1% predicted after 12 months of TIP (median 66 {IQR 51.25–77.75}) in all study participants (Z = − 1.23, p = 0.217). Paired analysis in a subgroup using TIS at baseline (median 68, {IQR 52.5–79}) who completed 12-months of TIP (median 66, {IQR 51.25– 77.5}) (n = 28) showed no significant difference in FEV1% predicted (p = 0.567). 3.4.4. TIS-naïve patients There was also no significant difference in the median number of intravenous antibiotic courses (p = 0.158) or change in FEV1% predicted (p = 0.98) between baseline TIS-users and TIS-naive patients after 12 months of TIP (data not tabulated). 27/78 (35%) were not using TIS at baseline. 12/27 were self-reported non-adherent to prescribed TIS, 6/27 were never prescribed TIS, and 9/27 were documented non-tolerant of TIS-8 due to cough or bronchospasm and 1 due to dysphonia. 9/12 non-adherent to prescribed TIS at baseline reported adherence to TIP therapy during the study (5 at 12 months, 2 at 9 months, 1 at 6 months, and 1 at 3 months). All 6 who were never prescribed TIS reported adherence to TIP. In the 9/27 who were non-tolerant of TIS, 5/9 (55%) tolerated TIP therapy,

While most of the existing data regarding inhaled therapies in CF have been derived from studies using clinical trial designs [8,24,25], this study describes the effectiveness of inhaled antibiotics in people with CF in a real world setting and falls into the category of Comparative Effectiveness Research (CER). CER involves “studying the effectiveness of an intervention in routine clinical practice to assist consumers, clinicians, purchasers, and policy makers to make informed decisions that will improve health care at both the individual and population levels” (Committee on Comparative Effectiveness Research Prioritization, Institute of Medicine). Clinical trials can only describe the efficacy of an intervention, i.e. whether the intervention works or not under optimal conditions, and may not demonstrate the effectiveness of an intervention in the real world. In particular, interpreting adherence data from clinical trials is difficult as adherence to the trial intervention by the participant is a prerequisite for continued involvement in the trial in most instances. While it has been postulated that the use of a more rapid delivery system would result in increased adherence to a given therapy, this is the first study comparing the effectiveness of the same inhaled antibiotic using 2 different delivery systems in patients with CF. The proportion of participants reporting “excellent adherence” in our study almost doubled after transition to TIP (43% to 83%) This finding further supports data regarding the existence of suboptimal adherence to nebulised therapy in people with CF [18]. This is important given a recent study that demonstrated that high TIS adherence (≥ to 4 cycles per year) showed a decreased risk of hospitalisations when compared to poor TIS adherence (≤ to 2 cycles per year) [26]. While it is important that we continue to develop beneficial therapies for our patients, it is equally important that we recognise the potential for a patient to become less adherent as treatment burden increases. Rapid delivery of therapies via inhaler can address this issue and may represent the future of inhaled antibiotics in CF. Our study demonstrated a statistically significant reduction in the number of intravenous antibiotic courses received using inhaled antibiotic therapy prospectively, over a 12-month period, compared with a 12-month period retrospectively using traditional nebulised therapy. Reducing the rate of pulmonary exacerbations is a key objective for CF clinicians. Recently published data suggests that patients with CF who experience frequent pulmonary exacerbations are at an increased risk of experiencing a decline in their lung function by 5% from baseline and that frequent pulmonary exacerbations are associated with an increased 3-year risk of death or lung transplant [27]. Up to 15% of adult [28] and 23% of paediatric [29] patients fail to recover to within 95% of baseline FEV1% predicted after a pulmonary exacerbation. We suggest that the decreased exacerbation rate seen after commencement of the faster delivery system may represent a downstream effect

Please cite this article as: Harrison MJ, et al, Inhaled versus nebulised tobramycin: A real world comparison in adult cystic fibrosis (CF), J Cyst Fibros (2014), http:// dx.doi.org/10.1016/j.jcf.2014.04.004

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of a relative increase in inhaled antibiotic dose received due to increased adherence to a less burdensome treatment regime. We chose to use intravenous antibiotic usage as a marker of exacerbation rate because the receipt of intravenous antibiotic therapy requires review by a clinician in the Cork Adult CF Centre. In our study population, patients could potentially access oral antibiotics without such a review. Of note, analysis of oral antibiotic usage comparing usage for a 12-month period retrospectively and 12-month period prospectively using TIP showed no significant difference between the cohorts. While we do not demonstrate an improvement in lung function, there is no significant difference in lung function seen during the study period. The majority of our participants were not tobramycin-naive at the time of study entry and so the effect of increased adherence to a more rapid delivery system on lung function may only become apparent over a longer period of follow-up. Demonstrating improvements in lung function in progressive lung disease can be difficult and may be beyond the scope of this type of study design. We observed a lower discontinuation rate in our study compared with that seen in the clinical trial [20] (14% vs. 27%). This difference may be explained by the fact that 36% of those who discontinued in the clinical trial did so due to withdrawal of consent or protocol violation, factors that were not relevant to our real world study. We reported discontinuation rates for the first 6-months of therapy to allow a valid comparison with the clinical trial, in which 6-month discontinuation data was also reported. We reported de novo oral candidiasis in 2 participants. Both cases resolved with first-line anti-fungal therapy allowing successful recommencement of inhaled therapies. One of the patients was taking concomitant inhaled corticosteroid therapy, while the other was using a short-acting beta-agonist inhaler on an “as required” basis. Oral candidiasis has not previously been reported as an adverse event associated with use of TIP. However, both of these patients were not TIS naïve suggesting the possibility of a drug delivery system-related phenomenon. The occurrence of oral candidiasis may signify the importance of good oral hygiene when using dry powder inhaled therapies with high deposition rates in the oropharynx [30]. 5. Conclusion Our real-world data strongly support the clinical trial data regarding the effectiveness of TIP therapy, and highlight the potential for a reduction in treatment burden to impact on health outcomes. 6. Limitations Our study had a number of limitations. There is a possibility that patient preference for TIP and the improved adherence scores demonstrated in our study result from, or are at least amplified by, a “honeymoon effect” where the initial period of use of any new therapy is associated with increased enthusiasm by the patient for the therapy. However, this effect is likely to be minimised over time and we did not see any waning of

adherence scores through the study period with adherence scores maintained in those on TIP therapy for 12 months. A limitation of real world studies is that one cannot guarantee complete data collection at all time points in individual participants. However, in 40 patients we have paired data at baseline and (at least) 12 months allowing longitudinal comparison over a 12-month period in this subgroup. The measurement of adherence in any study is difficult. Our study measured adherence by patient self-report, a method which has been shown to overestimate adherence to therapy in a CF population [18]. To minimise this effect, the questioning was carried out by a CF research nurse and not a clinician from the patients clinical care team. Care was taken to ensure that the self-reported adherence question was worded so as to ask about the “use” of TIP and so did not use the word adherence or any other terminology which may not have been understood by study participants. Patients were questioned specifically regarding their use of the inhaled tobramycin device as prescribed by the patient's clinician, without reference to any other treatments. Patients were encouraged to be honest at the time of questioning regarding their adherence and assured that the information given by them as part of this study would not be used by their clinician in the course of their routine clinical care. The relatively low level of self-reported adherence to TIS at study entry (43%), which approaches that seen in studies using electronic feedback monitors and prescription refill studies, may reflect a limited effect of responder bias in our study. There is also potential for recall bias with regard to patient's recall of their adherence with therapy. This may be more marked for recall of adherence during the 12-month period of TIS therapy at study entry compared with recall of adherence during the 3-month periods between study visits while on TIP therapy. However, the reduction in intravenous antibiotic usage demonstrated in the patients who reported improved adherence would support the existence of a genuine improvement in adherence in this group. References [1] Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol 2002;34(12112774):91–9100. [2] Kosorok MR, Zeng L, West SE, Rock MJ, Splaingard ML, Laxova A, et al. Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition. Pediatr Pulmonol 2001;32(4):277–87. [3] Courtney JM, Bradley J, McCaughan J, O'Connor TM, Shortt C, Bredin CP, et al. Predictors of mortality in adults with cystic fibrosis. Pediatr Pulmonol 2007;42(6):525–32. [4] Simmonds NJ. Ageing in cystic fibrosis and long-term survival. Paediatr Respir Rev 2013;14(Suppl. 1):6–9. [5] Plant BJ, Goss CH, Plant WD, Bell SC. Management of comorbidities in older patients with cystic fibrosis. Lancet Respir Med 2013;1(2):164–74. [6] Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 2003;168(8):918–51. [7] Quittner AL, Buu A. Effects of tobramycin solution for inhalation on global ratings of quality of life in patients with cystic fibrosis and Pseudomonas aeruginosa infection. Pediatr Pulmonol 2002;33(4):269–76. [8] Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, WilliamsWarren J, et al. Intermittent administration of inhaled tobramycin in

Please cite this article as: Harrison MJ, et al, Inhaled versus nebulised tobramycin: A real world comparison in adult cystic fibrosis (CF), J Cyst Fibros (2014), http:// dx.doi.org/10.1016/j.jcf.2014.04.004

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Please cite this article as: Harrison MJ, et al, Inhaled versus nebulised tobramycin: A real world comparison in adult cystic fibrosis (CF), J Cyst Fibros (2014), http:// dx.doi.org/10.1016/j.jcf.2014.04.004