Challenges in managing Pseudomonas aeruginosa in non-cystic fibrosis bronchiectasis

Accepted Manuscript Challenges in managing Pseudomonas aeruginosa in non-cystic fibrosis bronchiectasis Robert Wilson, Timothy Aksamit, Stefano Aliberti, Anthony De Soyza, J. Stuart Elborn, Pieter Goeminne, Adam T. Hill, Rosario Menendez, Eva Polverino PII:

S0954-6111(16)30131-7

DOI:

10.1016/j.rmed.2016.06.007

Reference:

YRMED 4942

To appear in:

Respiratory Medicine

Received Date: 20 November 2015 Revised Date:

24 May 2016

Accepted Date: 6 June 2016

Please cite this article as: Wilson R, Aksamit T, Aliberti S, De Soyza A, Elborn JS, Goeminne P, Hill AT, Menendez R, Polverino E, Challenges in managing Pseudomonas aeruginosa in non-cystic fibrosis bronchiectasis, Respiratory Medicine (2016), doi: 10.1016/j.rmed.2016.06.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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ACCEPTED MANUSCRIPT Challenges in managing Pseudomonas aeruginosa in non-cystic fibrosis bronchiectasis Robert Wilsona, Timothy Aksamitb, Stefano Alibertic, Anthony De Soyzad, J. Stuart

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Elborne, Pieter Goeminnef,g, Adam T. Hillh, Rosario Menendezi, and Eva Polverinoj Affiliations: aHost Defence Unit, Royal Brompton Hospital, London, UK, b

Mayo Clinic, Pulmonary Disease and Critical Care Medicine, Rochester, MN, US

c

Department of Pathophysiology and Transplantation, University of Milan,

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

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d

Newcastle University and Freeman Hospital, Newcastle upon Tyne, UK

e

Centre for Infection and Immunity, Queen’s University Belfast, Belfast, UK

University Hospital of Gasthuisberg, Department of Respiratory Disease, Leuven,

Belgium g

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f

Department of Respiratory Disease, AZ Nikolaas, St-Nikolaas, Belgium

h

Department of Respiratory Medicine Royal Infirmary of Edinburgh and the University

of Edinburgh, Edinburgh, UK

Pneumology Department, Hospital Universitario y politecnico La Fe, CIBERES,

Valencia, Spain j

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i

Fundaciò Clinic, IDIBAPS, CIBERES, Hospital Clinic de Barcelona, Barcelona,

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Spain

Correspondence: R. Wilson, Royal Brompton Hospital, London, SW3 6NP, UK

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E-mail: [email protected]

Abstract

Background

An Expert Forum was held at the 2014 European Respiratory Society International Congress to address issues involved in the management of Pseudomonas aeruginosa infection in patients with non-cystic fibrosis bronchiectasis (NCFB). Multiple studies have found that chronic P. aeruginosa infection is associated with more severe disease and higher morbidity and mortality. Overview Participants discussed appropriate management of P. aeruginosa infection at three

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stages: 1) first isolation, including eradication protocols; 2) during exacerbations; and 3) during chronic infection, including long-term antibiotic therapy to reduce the severity of symptoms and frequency of exacerbations. Topics covered included frequency of sputum cultures, antibiotic treatment at first isolation and for exacerbations, optimal use of inhaled antibiotics, indications for long-term therapy,

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and treatment regimens that may reduce the frequency or severity of symptoms. Electronic polling and roundtable discussions followed by expert insights were used to address these topics. Significant diversity in management practices was reported among different countries and centres, and in many cases clinical management was

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at variance with published guidelines. Conclusions

This Expert Forum identified standardised terminology, clinician training, additional

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research into management strategies, and the development of new drugs as areas requiring improvement for the optimal management of P. aeruginosa in NCFB.

Keywords

Antibiotics; airway inflammation; clinical management; lower airway infection; non-

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CF bronchiectasis; Pseudomonas aeruginosa.

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ACCEPTED MANUSCRIPT Introduction Non-cystic fibrosis bronchiectasis (NCFB) is a chronic respiratory disease characterised by chronic cough, sputum production, recurrent infection, and sometimes fatigue and haemoptysis. Patients with NCFB may have functional limitations due to reduced lung function, bronchial inflammation, and airway

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obstruction [1,2]. As the disease progresses, NCFB patients frequently experience significant morbidity, reduced quality of life, and high treatment burdens [2-4]. NCFB is associated with high mortality rates. In a recent study in Belgium, overall mortality was 20% during a 5-year period [5], and the mortality rate in England and Wales is

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reported to be increasing by 3% per year [6]. The prevalence of NCFB is higher in women and in older individuals and appears to be increasing over the last decade in

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Europe and the United States [4,7-9]. Estimates based on data from the CPRDGOLD database in the UK indicate that more than 1% of individuals 70 years of age and older have NCFB [7]. NCFB has diverse aetiology and this variability may affect management [3,10].

Although the pathophysiology of NCFB is not well defined, the vicious cycle model

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originally proposed by Cole [11], in which bacterial infection drives airway inflammation and disease progression, has been supported by numerous studies (reviewed by Mandal and Hill) [12], including a study by Chalmers et al. demonstrating that high bacterial loads in the airways of patients with NCFB are

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associated with markers of local and systemic inflammation [13]. Although a number of bacteria are associated with NCFB, Pseudomonas aeruginosa is one of the most

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common and significant pathogens in patients with this disease [14-16]. The presence of P. aeruginosa is associated with greater impairment in lung function [1722], increased airway inflammation [13], more frequent exacerbations [16], worse quality of life [22], greater risk of hospitalisation [22,23], and increased mortality [5,23,24]. The impact of Pseudomonas on the natural course of the disease has been confirmed by its identification as a key determinant of bronchiectasis severity in two recently-developed severity scoring systems, the Bronchiectasis Severity Index and the FACED score [23,25]. Accordingly, appropriate management of P. aeruginosa is an important concern throughout the course of NCFB.

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ACCEPTED MANUSCRIPT In clinical practice, there are three distinct points that present opportunities for managing P. aeruginosa infection in patients with NCFB: (1) at first isolation; (2) during exacerbations; and (3) during chronic P. aeruginosa infection (Figure 1). Figure 1. Intervention points in managing P. aeruginosa respiratory infection in patients with non-cystic fibrosis bronchiectasis. Adapted with permission from figure

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by Dr. Patrick Flume (Medical University of South Carolina, Charleston, South

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Carolina, US).

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There are limited data available to inform clinicians on optimal management at each point, and both national audit and anecdotal reports suggest that there is significant

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variation among practices [26].

To better understand current clinical practices for the management of P. aeruginosa in patients with NCFB, an Evening Expert Forum was held during the 2014 European Respiratory Society International Congress in Munich, Germany. This interactive seminar included an international group of practicing clinicians with a common interest in NCFB. Most (64%) of the 55 participants were from Europe, but other areas of the world, including Africa (5%), Asia (7%), Australia (7%), the Middle East (7%), South America (7%), and the United States (5%), were also represented. Of the 47 participants who responded to additional questions, 64% saw patients as part of a general respiratory clinic, 32% saw patients at a dedicated bronchiectasis clinic,

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ACCEPTED MANUSCRIPT and 4% saw patients as part of a cystic fibrosis (CF) clinic. These participants reported a wide variation in the estimated number of NCFB patients seen per year, ranging from <10 for 9% of participants to >50 for 32% of participants. Following a case presentation of a common scenario seen in an NCFB patient with recurring P. aeruginosa infection, a number of questions were posed and electronic

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“live” polling was used to capture responses. The clinicians divided into three groups, each focusing on one of the three points described above, for roundtable

discussions. Moderators presented the conclusions from each group, followed by

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expert feedback

The ensuing discussion provided an overview of the diversity in clinical opinion

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on current clinical practices (Table).

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among different centres and countries and offered an opportunity for expert feedback

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6 Table. Management of P. aeruginosa in patients with NCFB Question

Guidelines [1,27]

Current clinical practice*

First isolation

How often do you

• BTS: Respiratory tract

• At every visit (42%)

specimens should be

samples to culture?

obtained in all patients; frequency not specified • SEPAR: Cultures should be

(32%)

• When the sample is purulent (18%)

• Once a year (8%)

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performed at every checkup

• During an exacerbation

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send sputum

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Stage

• BTS: There are no studies to

Should P.

• Most clinicians attempt

Expert panel comments • Awaiting culture results during exacerbations may delay commencement of empiric antibiotic directed by prior surveillance microbiology • Once yearly cultures should be reserved for patients with very stable disease • “First isolation” may be

guide practice, but “an

eradication at first isolation,

misleading, as initial sputum

eradication be

attempt to eradicate seems

but the approach to therapy

culture may not represent

attempted?

pragmatic”

varies

the first appearance of P.

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aeruginosa

• SEPAR: An eradication

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attempt is desirable to delay

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chronic colonisation

What treatment do you use for P.

• BTS: Oral ciprofloxacin for 2 weeks; if further treatment

• Some clinicians did not consider eradication to be a

aeruginosa in a patient • A clinical trial is required to

viable option and so were

determine whether

more focused on reducing

eradication is achievable and

symptoms than on

associated with clinical

eradicating P. aeruginosa

improvements

• Oral ciprofloxacin (most common choice)

• Expert experience with guideline-recommended

aeruginosa

required, 2 weeks of IV anti-

• IV antibiotics

regimens varied with no

eradication?

pseudomonal antibiotics,

• Oral or IV antibiotic + inhaled

evidence for clear superiority

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7 Guidelines [1,27]

Current clinical practice*

nebulised colistin for 3 months, or nebulised colistin for 3 months with an additional 4 weeks of oral ciprofloxacin • SEPAR: 3 weeks of oral ciprofloxacin plus an inhaled

for up to 12 months During an

How do you define

exacerbation

an exacerbation?

• BTS : Acute deterioration †

with increased sputum volume or change in

• Other combination therapy

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antibiotic, which is continued

antibiotic

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Question

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Stage

• No overall consensus • Symptoms were the most frequent criteria for defining

Expert panel comments

of a specific regimen in clinical practice • Clinical trials are needed to address the best regimens for P. aeruginosa eradication in NCFB [28]

• Expert practice is generally consistent with guidelines • Pulmonary function tests and

an exacerbation; some

culture results may not

purulence, and worsening

required 2 or more

accurately reflect

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viscosity, increased sputum

local symptoms (increased

• Other definitions were based

exacerbations, as some

on pulmonary function tests

patients have only minimal

breathlessness) or systemic

or culture results

change in FEV1 during an

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cough, wheeze,

upset

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• SEPAR: Acute development and persistence of changes in sputum characteristics and/or increased breathlessness unrelated to other causes

NCFB exacerbation and well patients may have chronic bacterial colonisation

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8 Guidelines [1,27]

Current clinical practice*

Expert panel comments

How often do you

• BTS and SEPAR: Sputum

• Consistent with guidelines

• Expert practice is consistent

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Question

cultures with susceptibility

• Cultures usually repeated 4

cultures/

tests should be performed

to 8 weeks after treatment

susceptibility tests

for each exacerbation prior

during an

to administration of

exacerbation?

antibiotics

What antibiotics do

• BTS: Oral ciprofloxacin (14-

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perform sputum

• For ciprofloxacin-susceptible

with guidelines

• Ciprofloxacin-resistant

day course of 500 mg or 750

strains: generally oral

isolates pose a dilemma: it

patient with P.

mg twice daily depending on

ciprofloxacin

can be difficult to ascertain if

aeruginosa and

severity of infection) for

exacerbations?

ciprofloxacin-susceptible P.

strains: no consensus.

resistance is clinically

aeruginosa; ciprofloxacin-

Options included

relevant, or if P. aeruginosa

resistant isolates should be

azithromycin, ciprofloxacin,

is the only pathogen

treated with combination

nebulised colistin, and

involved. Accordingly, oral

therapy with anti-

outpatient IV antibiotics

ciprofloxacin is a viable

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you use to treat a

pseudomonal antibiotics

• SEPAR: Oral ciprofloxacin

• For ciprofloxacin-resistant

• Patients with severe

culture-determined

option for initial therapy, followed by IV antibiotics if

(14- to 21-day course of 750

hospitalised and treated with

the patient does not respond

mg twice daily) for mild

2 anti-pseudomonal drugs

clinically

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exacerbations are generally

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Stage

rd

• It is speculated that even

exacerbations; combination

(beta-lactam or 3 -

therapy with anti-

generation cephalosporin +

antibiotics without direct

pseudomonal antibiotics

aminoglycoside); therapy is

activity against P.

should be used for moderate

modified on the basis of

aeruginosa may result in

to severe exacerbations or

clinical response on day 3

clinical improvement by

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9 Question

Guidelines [1,27]

Current clinical practice*

patients who do not respond

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• BTS: Inhaled antibiotics are

How do you use

nd

Expert panel comments

affecting the “microbiome” or

to oral therapy

• No consensus on the optimal

reducing inflammation • In the experience of the

a possible component of 2 -

use of inhaled antibiotics.

during

line combination therapy

Scenarios for usage

tolerate inhaled antibiotics

included:

better than the literature

• SEPAR: Inhaled antibiotics

exacerbations in

are not listed as an option for

aeruginosa

treatment of exacerbations

How do you

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infections?

evaluate treatment success?

• BTS and SEPAR: Not addressed

expert panel, patients tend to

As continuation therapy

suggests; nevertheless,

after hospital discharge

inhaled antibiotics are

or outpatient treatment

probably best used as

with oral or IV

continuation therapy

antibiotics

following oral or IV

o

Mild exacerbations

antibiotics rather than as

o

As part of combination

acute therapy

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patients with P.

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inhaled antibiotics

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Stage

o

therapy for severe exacerbations o

Ciprofloxacin-resistant P. aeruginosa

• Based on improvement in

• Reliable, validated markers

symptoms and inflammatory

of treatment outcome are

markers

required to evaluate treatment success and develop new therapies

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10 Question

Guidelines [1,27]

Current clinical practice*

Expert panel comments

Chronic

What is the

• BTS: No definition specified

• Definitions varied; most

• Clinical trials vary with

infection,

definition of chronic

• SEPAR: 3 or more positive

including long-

infection?

cultures of the same

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Stage

common were: o

50% of sputum samples

chronic infection; this term should be standardised

microorganism within 6

positive for P.

therapy

months in samples collected

aeruginosa

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term antibiotic

at least 1 month apart

respect to definition of

o

2 to 3 consecutive positive sputum cultures

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following an attempt at eradication

Which patients are

• BTS: Should be considered

• Varying criteria, including:

• Expert practice is generally

in patients having ≥3

term antibiotic

exacerbations/year requiring

therapy with a high

therapy?

antibiotic treatment or

burden of symptoms

exacerbations per year as an

Patients who had been

indication for long-term

exacerbations that are

hospitalised, were older,

antibiotics

causing significant morbidity

or reported feeling more

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candidates for long-

patients with fewer

o

o

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• SEPAR: Should be considered in patients with

o

• Some considered >2

Generally >3 exacerbations/year

early relapse, hospitalisation,

(30% of participants

declining lung function, or

would consider long-

chronic Pseudomonas

term therapy after 2

infection

exacerbations/year)

• BTS and SEPAR: An inhaled

consistent with guidelines

unwell

recurrent exacerbations,

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Patients on optimal

• Macrolide (76%)

• Anti-pseudomonal inhaled

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11 Question

Guidelines [1,27]

Current clinical practice*

Expert panel comments

• Inhaled aminoglycoside

antibiotic preferred,

antibiotic should be first-line

term antibiotic

therapy for patients with

therapy in patients

chronic Pseudomonas

with chronic P.

infections in patients who

o

Nebulised colistin

acknowledged that

aeruginosa

meet criteria for long-term

o

Oral ciprofloxacin

macrolides worked well as

infection?

therapy

o

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recommended due to

success of longterm antibiotic therapy?

chronic therapy, but

ciprofloxacin-resistant

expressed concerns about

P. aeruginosa

resistance development

• Treatment was usually administered as continuous

potential side effects

therapy rather than

(especially in NTM) and side effects • There is currently no

alternating drugs or month

evidence to support

on/month off regimens

alternating or month on/month off regimens in NCFB

• BTS and SEPAR: Not

• Symptomatic improvement,

• Reliable, validated markers

including reduction in the

of treatment outcome are

number of exacerbations

required to evaluate

addressed

use to evaluate the

• The expert panel

Combination therapy for

concerns with resistance and

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measures do you

consistent with guidelines

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Which outcome

• Others:

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• BTS: Long-term oral ciprofloxacin is not

(24%)

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options for long-

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Stage

• Improvement in lung function

treatment success and

• Culture-based results do not

develop new therapies

factor into the assessment of outcome

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12 Question

Guidelines [1,27]

Current clinical practice*

Expert panel comments

What is the optimal

• BTS: Not addressed

• 3 months for eradication

• Not yet addressed in clinical

duration of long-

• SEPAR: Depends on how

term antibiotic

well the infection is

therapy?

controlled

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Stage

protocol or following IV antibiotics

• 1 year or longer for patients

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with more severe disease

• Some clinicians take patients

trials • No hard and fast rules; decisions are often driven by patient symptoms and preferences

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off therapy during the spring or summer, or cycle therapy during the year

*Percentages are based on polling results; qualitative summaries are based on presentations of roundtable summaries †

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The BTS definition is specifically for an exacerbation requiring antibiotics

BTS, British Thoracic Society; FEV1, forced expiratory volume in one second; IV, intravenous; NCFB, non-cystic fibrosis

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bronchiectasis; NTM, non-tuberculous mycobacteria; SEPAR, Spanish Society of Pulmonology and Thoracic Surgery.

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In addition, the Expert Forum identified an unmet need in the medical community for more comprehensive clinical guidelines on this topic, such as those that are being developed by the European Respiratory Society Bronchiectasis Guidelines Task Force [29]. Finally, areas requiring future research were discussed, with an emphasis on the need for standardised definitions – which remain an area of debate

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[30] – and practices in NCFB clinical research and an international registry to allow advancement of the knowledge base and accurate translation to clinical practice.

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Management of P. aeruginosa infection at first isolation

Much of the clinical practice involved in managing P. aeruginosa in patients with NCFB is derived from studies conducted in CF, as there are limited data to guide

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NCFB practitioners [2,31]. In CF, it is clearly established that early infection with P. aeruginosa is associated with worse outcomes (reviewed by Stuart et al.) [32], and eradication is associated with clinical benefits, including improved pulmonary function and reduced hospitalisation [33-36]. Accordingly, sputum cultures for CF patients are screened for P. aeruginosa on a regular basis; European guidelines

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recommend that airway cultures be obtained at every visit [37]. For NCFB, the benefits and feasibility of early P. aeruginosa eradication attempts are still debated, as this patient population may have been colonised with this pathogen for extended periods of time before initial detection, and the frequent presence of comorbid

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conditions may complicate management decisions. In addition, although spontaneous clearing of Pseudomonas infection in CF is considered an unusual

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event, intermittent isolation of P. aeruginosa with spontaneous clearing of the infection (as judged by sputum culture) is not considered uncommon in NCFB. In a recent study of Pseudomonas persistence in patients with NCFB, 16 of 47 patients (34.0%) who were colonised with P. aeruginosa (defined as isolation on 2 or more occasions, at least 3 months apart, within a 1-year period) subsequently became culture negative during follow-up without any specific eradication treatment [20].

Sputum cultures

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ACCEPTED MANUSCRIPT Significant diversity in clinical practice patterns for monitoring sputum cultures in patients with NCFB was revealed during this meeting (Figure 2).

Figure 2. Respondents’ responses to the question “How often do you send sputum

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for culture?” in live electronic polling.

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In electronic polling responses to the question “How often do you send sputum for culture?” 42% of clinical practitioners reported that they send a sample to the lab at

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every outpatient visit, in keeping with the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) recommendations that sputum cultures be obtained at each check-up [27]. The second most common answer (32%) was “only during an exacerbation.” The experts noted that obtaining sputum cultures only during an exacerbation may impair the effective use of past microbiology to guide empiric treatment. Eight percent of participants chose once yearly, but the experts recommended that this frequency be used only in extremely stable patients. Roundtable discussions on management following first isolation of P. aeruginosa emphasised the need for a high-quality sputum sample, obtained during physiotherapy if possible. The potential need for more sensitive methods for P.

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aeruginosa identification, such as molecular tests, was also discussed. Participants felt that if first isolation did prove to offer the best chance of eradication, as is the case for CF, then more sensitive methods of P. aeruginosa identification would be important in facilitating early detection. Discussion focused on a recent study which found that standard culture methods only detect about one-third of samples identified

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as positive for P. aeruginosa by molecular methods [16]. The expert panel noted, however, that the presumed benefits of more sensitive detection methods are based on the assumption that molecular methods and culture results represent different positions on the same clinical continuum, and this hypothesis is yet to be proven.

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The key information derived from the sputum sample was qualitative in nature, namely pathogen identification. The roundtable participants did not consider

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quantitative information (e.g., colony counts) to be relevant to treatment choices. Antibiotic susceptibility tests were generally performed for the first isolation of P. aeruginosa, but not necessarily for routine chronic infections. Concept of P. aeruginosa eradication

Although European CF guidelines support eradication protocols for first isolation of

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P. aeruginosa [37,38], the evidence base for NCFB is less clear. As a result, there were differing opinions at this Expert Forum concerning whether P. aeruginosa eradication attempts at first isolation are achievable or useful. One expert noted that

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the concept of “first isolation” was a difficult one in this older population, and heavily dependent on the frequency of testing and accuracy of the lab results. This observation highlights the importance of the significant variance in the frequency of

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obtaining cultures revealed in earlier discussion. Although data in NCFB are limited, a recent study suggests that eradication of P. aeruginosa in NCFB patients may be associated with improvements in health in some patients. This single-centre retrospective study involved 30 NCFB patients and found that eradication protocols were initially successful in 80%. However, approximately half of these patients had subsequent positive P. aeruginosa cultures at a median of 6.2 months after eradication. Patients treated with eradication protocols had a reduced frequency of exacerbations in the year following eradication, but there was no difference in hospitalisation [39]. Although these data suggest

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some benefit from eradication protocols, randomised clinical trials with larger patient populations will be required to determine the outcomes associated with P. aeruginosa eradication following first isolation in NCFB patients. Although the participants generally believed that such trials would be justifiable and valuable, they

Treatment options including eradication protocols

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agreed there would be significant practical difficulties in conducting these studies.

Treatment of P. aeruginosa following first isolation varied significantly among

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clinicians at this Expert Forum. This diversity reflected differing local guidelines and opinions on the feasibility of eradication as well as the lack of a clearly preferred

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eradication protocol for CF. In a recent Cochrane review of CF therapies used for P. aeruginosa eradication, various treatment regimens with inhaled antibiotics (colistin or tobramycin), with or without oral ciprofloxacin, appeared to have comparable efficacy, although some of the studies were underpowered to show a difference between therapies [40].

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Many of the roundtable participants use oral ciprofloxacin for P. aeruginosa eradication therapy in NCFB patients. However, more aggressive strategies, such as combination therapy with oral or intravenous (IV) antibiotics, sometimes with the addition of inhaled antibiotics, were also employed by the participants. The SEPAR

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guidelines recommend eradication of P. aeruginosa with 3 weeks of oral ciprofloxacin plus an inhaled antibiotic that is continued for 3 to 12 months [27]. The

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British Thoracic Society (BTS) NCFB guidelines note that although there is no evidence to support the benefits of eradication, an eradication attempt is a reasonable intervention; 2 weeks of oral ciprofloxacin is the recommended treatment. If this therapy fails to eradicate Pseudomonas, further treatment can be considered, such as 2 weeks of IV anti-pseudomonal antibiotics, nebulised colistin for 3 months, or nebulised colistin for 3 months with an additional 4 weeks of oral ciprofloxacin [1]. Participants reported that they judge the success of treatment by both sputum cultures and clinical improvement. Sputum cultures are typically performed by participants before and approximately 4 to 6 weeks after treatment. Most participants

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ACCEPTED MANUSCRIPT require 2 or 3 negative sputum samples over the next year before they consider P. aeruginosa to be eradicated. The expert panel agreed with this definition but noted

that reliable, validated definitions of eradication and treatment outcome are required to evaluate treatment success and allow the development of new therapies for NCFB

Management of P. aeruginosa during an exacerbation

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[41].

Exacerbations are a significant complication in patients with NCFB and are

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associated with reductions in lung function and quality of life [19,42]. NCFB patients with P. aeruginosa infections have more frequent exacerbations and more severe

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disease [16,20,23,25]. Accordingly, optimal management of exacerbations is a critical topic for clinical practitioners with NCFB patients. As with P. aeruginosa eradication protocols, exacerbation treatment choices for NCFB often rely on research conducted in CF patients. However, CF practices have a rather disappointing record of success in NCFB, and in some cases unexpected adverse events have occurred [43]. For instance, inhaled tobramycin, an established CF

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therapy, was found to result in unexpected pulmonary adverse events in NCFB patients, including increased cough and wheezing [44]. Although it is becoming increasingly clear that management practices for other diseases cannot always be

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directly transferred to NCFB, there are few clinical studies available in patients with

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NCFB to fill the current knowledge gap.

Defining an exacerbation There was no consensus on how to define an exacerbation in the groups assigned to this topic. Most roundtable participants rely primarily on symptoms, such as increasing sputum volume, increasing sputum purulence, breathlessness, fatigue, and fever, and some specified that they require two or more significant symptoms to classify the event as an exacerbation. Other participants look at changes in pulmonary function tests or base their assessment on culture results or radiographs. However, the expert panel emphasised that pulmonary function tests and culture

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results may not accurately reflect exacerbations, as in many patients there is either no change or only minimal change in FEV1 during an NCFB exacerbation, and well patients may still have chronic bacterial colonisation. The BTS guidelines define an exacerbation requiring antibiotics as acute deterioration (usually over several days) with all 3 of the following features: 1)

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increased sputum volume or change in viscosity; 2) increased sputum purulence; and 3) worsening local symptoms (increased cough, wheeze, breathlessness) or systemic upset [1]. The SEPAR guidelines define an exacerbation as the acute

development and persistence of changes in sputum characteristics and/or increased

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breathlessness unrelated to other causes [27]. Clinical trials use a variety of different definitions for exacerbation, including a requirement for systemic antibiotics. The

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expert panel noted that standardisation of this term would allow different treatments and management practices to be compared more accurately across different studies.

Sputum cultures

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The roundtable participants concurred that optimal management of exacerbations includes a sputum sample with antibiogram data for each exacerbation prior to administration of antibiotics, in agreement with BTS and SEPAR guidelines [1,27]. Until this information is available, empiric antibiotic therapy is usually guided by past

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culture data. Post-exacerbation cultures are usually repeated approximately 4 to 8

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weeks after treatment.

Treatment options

Roundtable participants usually treat patients with mild exacerbations and a P. aeruginosa infection known or presumed to be ciprofloxacin-susceptible as outpatients, typically with oral ciprofloxacin as recommended by the BTS and SEPAR guidelines [1,27]. BTS guidelines recommend a 14-day course of oral ciprofloxacin at a dose of 500 or 750 mg twice daily depending on the severity of infection [1], and SEPAR guidelines recommend oral ciprofloxacin at 750 mg twice

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daily for 14 to 21 days [27]. It should be noted, however that these recommendations are based on limited evidence due to the paucity of data from randomised placebocontrolled trials of antibiotics in NCFB [1]. Patients with more severe exacerbations, such as those with hypoxaemia or respiratory distress, are often hospitalised, although some centres operate a home

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delivery IV antibiotic programme. Treatment for severe exacerbations varied among participants and included monotherapy or dual anti-pseudomonal therapy. Most

participants modified regimens on the basis of clinical response on the third day of treatment; they agreed that not all patients will show signs of improvement by this

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time point, but patients who have worsened should be changed to an alternative therapy without further delay. If the clinical response is satisfactory, treatment is

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continued for at least 10 days. If the clinical response is suboptimal, the clinicians change antibiotics, usually by opting for a broader spectrum antibiotic or converting to combination therapy. The assessment of clinical response is typically based on improvement in symptoms and blood inflammatory markers. The roundtable participants felt that better markers of treatment response would be helpful.

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Participants usually scheduled post-exacerbation follow-up visits approximately one month after the event. During this appointment, they obtain sputum samples and review self-management of the disease and adherence to treatment. Participants emphasised the need for effective and clear communication with the patient and the

management.

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patient’s primary care physician concerning exacerbation and post-exacerbation

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Although treatment of ciprofloxacin-sensitive isolates was similar among different centres, there was no consensus on the preferred option for treatment of ciprofloxacin-resistant P. aeruginosa. Interactive electronic polling was used to explore the choice of treatment for a patient with a ciprofloxacin-resistant isolate and a non-severe chest infection (Figure 3). Figure 3. Respondents’ choice of treatment for a non-severe exacerbation potentially associated with ciprofloxacin-resistant P. aeruginosa in live electronic polling.* [Note to editor: text to be displayed underneath Figure 3]

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ACCEPTED MANUSCRIPT *The scenario was presented as: •

Patient unwell with a chest infection, not severe, sputum culture one month ago

•

Pseudomonas aeruginosa resistant to ciprofloxacin—what would you

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prescribe?

Dosing and duration of treatment choices were as follows: ciprofloxacin 750 mg bd

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for 14 days; co-amoxiclavulanate (standard dose for your country) for 14 days; azithromycin 500 mg od 6 days, then 250 mg od 6 days; colistin nebulised 1 mU bd

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one month; outpatient IV antibiotic e.g. ceftazidime 2 g td 10 days; something else.

The most frequent choice of therapy was azithromycin (23%) followed by “something else” (21%), but ciprofloxacin, nebulised colistin, and outpatient IV antibiotics were other popular options, each receiving 15% of the vote. The BTS guidelines recommend combination antibiotics for patients with P. aeruginosa resistant to one or more anti-pseudomonal antibiotics [1], and the SEPAR guidelines recommend combination therapy with IV anti-pseudomonal antibiotics for patients with severe exacerbations and those who do not respond to oral therapy [27].

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The expert panel noted that ciprofloxacin-resistant P. aeruginosa often represents a conflict between therapeutic choices based on susceptibility results and those based on pragmatic considerations. Although ciprofloxacin-resistant P. aeruginosa may be treated more effectively with IV antibiotics, it is likely that many patients would respond to less aggressive treatment options, as in vitro susceptibility findings do not

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always translate into clinical response in NCFB. Accordingly, at several centres, the first line of treatment for P. aeruginosa is an oral quinolone, even if the isolate is

ciprofloxacin-resistant. Patients who do not respond are switched to domiciliary IV therapy with anti-pseudomonal drugs.

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Another rationale for treating P. aeruginosa exacerbations with oral antibiotics

lacking specific activity against this pathogen is the potential effect of the antibiotic

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on microbiome interactions. Molecular methods indicate that the NCFB microbiome comprises multiple potential pathogens with complex interactions [14,45,46]. Unlike more clear-cut models of lung infection, such as pneumonia, in vitro tests of microbial susceptibility are not necessarily predictive of clinical response [47]. Antibiotic treatment of NCFB patients is associated with demonstrable reductions in systemic and airway inflammation [13]. It is thus plausible that even antibiotics not

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specifically directed at P. aeruginosa, such as co-amoxiclavulanate or macrolides

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could change the microbiome and improve symptoms associated with exacerbations.

Inhaled antibiotics in the treatment of exacerbations

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The use of inhaled antibiotics during exacerbations generated extensive discussion. Compared with oral or IV antibiotics, inhaled antibiotics reach high concentrations in the airways with reduced systemic absorption and toxicity [48]. A recent metaanalysis in patients with NCFB found that 4 weeks of inhaled antibiotics resulted in an approximately 1000-fold decrease in sputum bacterial load and was approximately four times more likely than placebo to eradicate bacteria from sputum [48]. Participants at the Expert Forum use inhaled antibiotics in a variety of different ways. The vast majority use nebulised agents. Some employ these agents to treat mild exacerbations or as a component of combination therapy in patients with more severe disease, but others utilise inhaled therapy only in patients resistant to

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ACCEPTED MANUSCRIPT ciprofloxacin. In some centres, patients are switched to inhaled antibiotics as continuation therapy upon hospital discharge. The inhaled antibiotic chosen depended on location and funding considerations. In the BTS guidelines, inhaled

antibiotics are a possible component of 2nd-line combination therapy (in addition to an IV anti-pseudomonal agent) for acute exacerbations in patients with P.

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aeruginosa infection. In addition, inhaled antibiotics are recommended as 2nd-line therapy at first isolation and as 1st-line therapy for chronic infection with P.

aeruginosa [1]. The SEPAR guidelines do not list inhaled antibiotics as an option for treatment of exacerbations, although they are recommended for initial and chronic

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infections with Pseudomonas [27].

There was no clear consensus on the continued use or cessation of nebulised

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agents during an exacerbation with significant bronchospasm, and the participants expressed some concern about the ability of sicker patients to tolerate inhaled antibiotics. The meta-analysis of inhaled antibiotics in NCFB reported an overall bronchospasm rate of 10% in seven trials involving 526 patients; the use of inhaled aminoglycosides was associated with a 4.78-fold increase in the risk of bronchospasm, but ciprofloxacin and colistin were not significantly associated with

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this adverse event [48]. However, the expert panel concurred that some patients tended to tolerate inhaled tobramycin quite well, despite the high rates of bronchospasm reported in the literature.

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Inhaled antibiotics in the prevention of exacerbations Two formulations of inhaled ciprofloxacin are currently in development to reduce

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exacerbations: Ciprofloxacin dry powder for inhalation (DPI) and a liquid combination formulation consisting of a solution of liposomal ciprofloxacin mixed with a solution of un-formulated (free) ciprofloxacin. Ciprofloxacin DPI is delivered twice-daily in one to two breaths via a small, hand-held, breath-actuated inhaler while free/liposomal ciprofloxacin is delivered via nebulisation. Results of Phase III trials will help identify those patients who may benefit from inhaled forms of the drug in this scenario [4952].

Management of chronic infection with P. aeruginosa

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As discussed previously, chronic colonisation with P. aeruginosa is associated with more severe disease and worse patient outcomes [5,20,22,23,25]. Although to date no rigorous clinical data support the benefits of treating chronic P. aeruginosa infections, there are strong theoretical reasons for doing so as well as anecdotal evidence from clinical practice [1]. As might be expected from the lack of data on this

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topic, there was a wide range of management strategies for chronic P. aeruginosa infections among the clinicians at the Expert Forum. Potential therapeutic options for patients with chronic P. aeruginosa infections are in development (see clinicaltrials.gov for more information).

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Defining chronic infection

The roundtable participants at this Expert Forum generally defined chronic infection

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as at least 50% of sputum cultures positive for P. aeruginosa over a one year period, or, alternatively, as two to three consecutive positive sputum cultures following an attempt at eradication. The SEPAR guidelines define chronic infection as three or more positive cultures for the same microorganism within 6 months in samples collected at least 1 month apart [27], while the BTS guidelines state that varying

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definitions exist [1]. The expert panel noted that there are various definitions for chronic P. aeruginosa infection in CF, including the Copenhagen definition and the Leeds criteria (reviewed by Pressler, et al.) [53], but that these are based on more frequent sputum cultures (7 to 10 per year) and therefore may not be directly

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applicable to NCFB. Clinical trials in NCFB differ with respect to criteria for chronic infection, and a uniform definition should be established for this term to facilitate

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comparisons among research studies and standardise care. Although increasing levels of antibodies to Pseudomonas are risk factors and surrogate markers for chronic infection in patients with CF (reviewed by Presser et al.) [53], the value of monitoring anti-pseudomonal antibodies has not been established for NCFB and was not commonly performed by the participants.

Indications for long-term antibiotic therapy In recognition of the impact of exacerbations on patient well-being, the BTS guidelines identify reductions in exacerbations as the aim of chronic management

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ACCEPTED MANUSCRIPT [1]. The roundtable participants stated that they frequently instituted long-term antibiotic therapy in patients with NCFB to reduce the frequency and severity of symptoms, including exacerbations. The decision to initiate long-term antibiotic therapy in patients with chronic P.

aeruginosa typically depends on the burden of symptoms. The clinicians considered

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patients on optimal therapy (such as physiotherapy and therapy to promote

expectoration) who continue to experience significant symptoms, including frequent exacerbations, a high volume of sputum, purulent sputum, poor lung function, and fatigue, to be good candidates for long-term therapy. Other key considerations

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include hospitalisations, age, inflammatory markers, and the patient’s overall feeling of ill health.

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In interactive electronic polling, three exacerbations per year was the most common threshold required by participants before initiating long-term antibiotic therapy (46%),

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although two exacerbations was sufficient for 30% of the respondents (Figure 4).

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Figure 4. Respondents’ responses concerning the number of exacerbations per year generally required before beginning long-term antibiotic therapy (with inhaled

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antibiotic and/or azithromycin) in live electronic polling.

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Together, these data indicate a general threshold of two or more exacerbations per year for the majority (76%) of respondents. The BTS guidelines recommend consideration of long-term antibiotics in patients having three or more exacerbations

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per year requiring antibiotic therapy or patients with fewer exacerbations that are causing significant morbidity [1], while the SEPAR guidelines recommend that prolonged antibiotics therapy should be considered in patients with recurrent

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exacerbations, early relapse, hospitalisation, declining lung function, or chronic Pseudomonas infection [27].

Long-term antibiotic therapy for patients with chronic P. aeruginosa infection Electronic polling was also used to assess the participants’ choice of therapy in patients with chronic P. aeruginosa infection. When asked whether they generally preferred long-term therapy with a macrolide, which has been shown to reduce the overall number of exacerbations [54-56], or with an inhaled antibiotic that would

26

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target Pseudomonas in patients with chronic infections, macrolides were chosen by 76% of respondents vs 24% for an inhaled antibiotic. The preference for macrolides was attributed to the strong evidence base for the benefit of low-dose chronic therapy with these agents in NCFB [54-56] and the lack of high quality evidence for inhaled antibiotics. Participants also noted the simplicity and acceptability of chronic

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macrolide use [57]. The choice of macrolide varied among participants and countries due to availability, cost, and concerns about side effects, including cardiac toxicity and adverse effects on hearing. Some participants stated that they are reluctant to institute this therapy in patients with comorbid cardiac disease. Patients who fail or

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cannot tolerate macrolides are typically switched to nebulised colistin or gentamicin. In contrast to the preference of participants for macrolides, the majority of the expert

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panel preferred an anti-pseudomonal inhaled antibiotic as long-term antibiotic therapy due to concerns that the widespread use of chronic macrolide therapy may promote resistance to these drugs in the airway microbiota, particularly in nontuberculous mycobacteria (NTM) [58]. The experts agreed that it is imperative to screen patient’s sputum for NTM before commencing macrolide therapy. Because there are few effective treatment options for NTM infection, widespread macrolide

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resistance in NTM could have dire consequences. The BTS and SEPAR guidelines both recommend an inhaled antibiotic as the first option for patients with chronic Pseudomonas infections who meet criteria for long-term antibiotic therapy [1,27].

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A recent meta-analysis reported that NTM has an overall prevalence of 9.3% in patients with bronchiectasis [59], but some studies have reported rates as high as

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37% [60]. NTM infections frequently go undetected. In a recent study, 14 of 126 (11%) individuals undergoing lung volume reduction surgery had histological evidence of mycobacterial infection despite an absence of clinical symptoms suggestive of NTM [61]. Before initiation of long-term macrolide therapy, NTM lung disease should be thoroughly screened for and excluded on the basis of clinical, radiographic, and microbiologic criteria [62]. Additional choices for long-term antibiotic therapy mentioned by the participants included oral ciprofloxacin or levofloxacin. This is counter to the BTS guidelines, which caution against the use of long-term oral ciprofloxacin due to the potential development of antibiotic resistance and adverse events [1].

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ACCEPTED MANUSCRIPT Inhaled antibiotics might afford a means to overcome bacterial resistance if the optimal dosing regimen is used [63]. Pharmacokinetic data show that higher

concentrations of inhaled vs systemic ciprofloxacin are found in sputum and that the terminal half-life, clearance and volume of distribution are also greater than previously reported values for an oral or IV therapeutic dose [64,65]. It is this

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increase in drug concentration at the site of infection that is key to the avoidance of resistance. The lower systemic exposure of inhaled vs oral formulations is also important when considering resistance. Oral ciprofloxacin is mainly absorbed

through the gut and results in high systemic exposure [66]. This can negatively

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impact on gut flora and put selection pressure on non-Pseudomonal organisms [67]. The peak systemic concentration measured in healthy volunteers was 0.056mg/L after Ciprofloxacin DPI 32.5 mg [64], and 0.169 mg/L after administration of one

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dose (210 mg ciprofloxacin) of the nebulized ciprofloxacin mixed formulation (60 mg as free and 150mg liposomal ciprofloxacin) [68]. As inhaled antibiotics have low systemic exposure it can be expected to have a reduced impact on the gut microbiome and resistance rates. Data from recent and ongoing studies of inhaled ciprofloxacin for the reduction of exacerbations in NCFB will further aid

Outcome measures

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understanding of the impact of inhaled ciprofloxacin on resistance patterns.

Success of long-term antibiotic therapy was loosely defined as “the patient feeling

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better.” The round table participants agreed that symptomatic improvements, such as decreased exacerbations, reduced sputum volume, and improvements in lung

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function, are more important in determining the success and continuation of therapy than culture-based results. The expert panel noted that this is an area not addressed by guidelines and another term that lacks a standardised definition. Recently validated patient-reported assessments of symptoms, such as the Quality of Life Questionnaire-Bronchiectasis [69,70], may help allow more accurate evaluations of symptomatic improvements.

Duration of long-term antibiotic treatment

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ACCEPTED MANUSCRIPT The roundtable participants typically continue long-term antibiotic treatment for

approximately 3 months in patients undergoing an eradication attempt or following IV antibiotics, and for a year or more in patients with more severe disease. Some clinicians support the patient’s choice of a treatment holiday and take patients off therapy in the spring or summer months, while others give the patient 2 or 3 cycles

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of therapy over the course of the year. For inhaled agents, continuous therapy was more common than alternating agents or month on/month off regimens, in contrast to common practice in CF patients and NCFB clinical trials. Decisions concerning the duration of chronic treatment are made with the patient’s input and are often guided

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by the prevailing seasonality of respiratory viruses. BTS guidelines do not address the duration of long-term therapy, while SEPAR guidelines state that it depends on

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how well the infection is controlled [1,27].

Improving the management of P. aeruginosa in NCFB

On the basis of the roundtable discussions at this Expert Forum, the attendees concluded that there was a wide variety of approaches to the management of P.

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aeruginosa in NCFB and a need for greater international collaboration to ensure appropriate dissemination of information on this important topic. The roundtable discussions also highlighted the importance of standardised terminology, including uniform definitions for eradication, exacerbation, chronic infection, treatment

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response, and outcomes of long-term antibiotic therapy. Widely-accepted, common definitions are essential so that treatment practices and outcomes can be accurately

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and rigorously evaluated in clinical trials and compared among different centres. The participants also identified several clinical research questions that need to be addressed, including: •

Do P. aeruginosa eradication protocols provide long-term benefits to NCFB

patients? •

Is culture-directed antibiotic therapy more effective than empiric therapy during exacerbations?

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ACCEPTED MANUSCRIPT •

Is long-term suppressive antibiotic therapy associated with increased antibiotic resistance?

•

What is the optimal regimen and duration for long-term antibiotic treatment regimens?

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Although retrospective studies and analyses of bronchiectasis registries may be able to address some of these research questions, randomised clinical trials in NCFB will be required for definitive answers. The European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC), which was created to promote research and

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education in the field of bronchiectasis, provides a network that will hopefully

encourage and facilitate clinical trials in Europe (see https://www.bronchiectasis.eu/ for more information). In addition, results from studies of new therapeutic agents will

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hopefully broaden available treatment options and provide additional insights into the effects of therapy on the course of the disease.

Conclusions

This Expert Forum revealed significant diversity among different centres and

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countries with respect to the management of P. aeruginosa-infected NCFB patients. These differences are predominantly driven by the lack of a robust evidence base. Sharing treatment insights and expert guidance may help improve patient management. The care of NCFB would be improved by clinician training on this

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topic, standardised terminology, and clinical research designed to address key questions and provide additional information on the most beneficial therapeutic

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options.

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ACCEPTED MANUSCRIPT NOTE ON TERMINOLOGY Dr Elborn prefers the use of the designation of Bronchiectasis rather than non-CF bronchiectasis as discussed in Chalmers and Elborn, 2015 [30].

AUTHORSHIP

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All authors contributed significantly to manuscript preparation. All authors have approved the final draft.

FINANCIAL DISCLOSURES

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The moderators and expert panel for this forum (see Acknowledgements) received compensation for their participation from Bayer HealthCare, Germany. Prof. Wilson has received fees from Bayer for lectures and advisory board memberships. Prof.

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Aliberti has received fees from Bayer and AstraZeneca for advisory board memberships. Dr. De Soyza has received fees from Almirall, AstraZeneca, Bayer, Chiesi, Forest Laboratories, GSK, and Novartis for lectures and advisory board memberships and educational grant support from AstraZeneca, Gilead, Bayer, Forest Laboratories, and Novartis for research into bronchiectasis. Dr Goeminne has

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received fees from Bayer for advisory Board membership. Dr Elborn has received funding from Bayer, Novartis and Basilea for consultancy. All payments were made to Queens University Belfast.

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FUNDING

Bayer HealthCare, Germany, sponsored the Evening Expert Forum that was the

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basis for this publication and provided funding for manuscript support by Highfield Communication, Oxford, England and Fusion MD, Montreal, Canada. Dr. De Soyza acknowledges the support of EMBARC and the Medical Research Council funded BronchUK collaborative for peer support and advice in bronchiectasis.

ACKNOWLEDGEMENTS The Evening Expert Forum was chaired by Professor Robert Wilson (Royal Brompton Hospital, London, UK). The moderators for this expert forum were Dr. Stefano Aliberti (University of Milan Bicocca, Clinica Pneumologica, AO San Gerardo, Monza, Italy), Dr. Anthony De Soyza (Newcastle University and Freeman

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Hospital, Newcastle upon Tyne, UK), Professor J. Stuart Elborn (Queen’s University Belfast, Belfast, UK), Dr. Pieter Goeminne (University Hospital of Gasthuisberg, Leuven, Belgium), Dr. Rosario Menendez (Hospital Universitario y politecnico La Fe, CIBERES, Valencia, Spain), and Dr. Eva Polverino (Fundacio Clinic, IDIBAPS, CIBERES, Barcelona, Spain), and the expert panel consisted of Dr. Timothy Aksamit

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(Mayo Clinic, Rochester, MN, US), Professor J. Stuart Elborn, and Dr. Adam T. Hill (Department of Respiratory Medicine Royal Infirmary of Edinburgh and the University of Edinburgh, Edinburgh, UK). The authors would like to thank all of the participants in the Evening Expert Forum for their insightful comments and Dr. Patrick Flume

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(Medical University of South Carolina, Charleston, South Carolina, US) for granting

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permission to adapt his figure.

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adult bronchiectasis. Chest 2006; 130: 1503-1510. 45 Purcell P, Jary H, Perry A, Perry JD, Stewart CJ, Nelson A, Lanyon C, Smith DL, Cummings SP, De Soyza A. Polymicrobial airway bacterial communities in adult bronchiectasis patients. BMC Microbiology 2014; 14: 130 46 Rogers GB, Shaw D, Marsh RL, Carroll MP, Serisier DJ, Bruce KD. Respiratory microbiota: addressing clinical questions, informing clinical practice. Thorax 2015; 70: 74-81. 47 Dickson RP, Martinez F, Huffnagle GB. The role of the microbiome in exacerbations of chronic lung diseases. Lancet 2014: 384: 691-702.

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49 US National Institutes of Health Clinical Trial 2016. Ciprofloxacin Dry Powder for Inhalation in Non-cystic Fibrosis Bronchiectasis (Non-CF BE) (RESPIRE 1). Available from https://clinicaltrials.gov/ct2/show/NCT01764841. Last accessed

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Highlights • P. aeruginosa is linked to severe disease, worse quality of life and higher mortality • Robust evidence for optimal treatment of P. aeruginosa infection in

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NCFB is lacking

• The importance and feasibility of P. aeruginosa eradication is not yet understood

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• Potential therapies for chronic P. aeruginosa infection are in

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development