Antimicrobial resistance in cystic fibrosis: A Delphi approach to defining best practices

Antimicrobial resistance in cystic fibrosis: A Delphi approach to defining best practices

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ARTICLE IN PRESS

JID: JCF

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Journal of Cystic Fibrosis xxx (xxxx) xxx

Contents lists available at ScienceDirect

Journal of Cystic Fibrosis journal homepage: www.elsevier.com/locate/jcf

Original article

Antimicrobial resistance in cystic fibrosis: A Delphi approach to defining best practices Edith Zemanick a, Pierre–Régis Burgel b,l, Giovanni Taccetti c, Alison Holmes d, Felix Ratjen e, Catherine A. Byrnes f, Valerie J. Waters g, Scott C. Bell h, Donald R. VanDevanter i, J. Stuart Elborn j, Patrick A. Flume k,∗ , on behalf of the Antimicrobial Resistance International Working Group in Cystic Fibrosis a

Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States Division of Respiratory Medicine and Adult Cystic Fibrosis Center, Assistance Publique Hôpitaux de Paris and University Paris Descartes, Paris, France c Cystic Fibrosis Center, Department of Pediatrics, University of Florence, Italy d National Institute for Health Research Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, Imperial College London. United Kingdom e Division of Respiratory Medicine, Department of Pediatrics, Translational Medicine,Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Canada f Department of Paediatrics, University of Auckland & Respiratory Department, Starship Children’s Health, Auckland, New Zealand g Division of Infectious Diseases, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada h Department of Thoracic Medicine, The Prince Charles Hospital and QIMR Berghofer Medical Research Institute, Brisbane, Australia i Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, United States j Imperial College and Royal Brompton Hospital, London and Queen’s University Belfast, United Kingdom k Departments of Medicine and Pediatrics, Medical University of South Carolina, Charleston, SC, United States l ERN-Lung cystic fibrosis network b

a r t i c l e

i n f o

Article history: Received 24 April 2019 Revised 10 August 2019 Accepted 2 October 2019 Available online xxx Keywords: Cystic fibrosis Antimicrobial resistance Consensus

a b s t r a c t Background: Antimicrobial susceptibility testing (AST) is a cornerstone of infection management in cystic fibrosis. However, there is little evidence that AST predicts the clinical outcome of CF antimicrobial treatment. It has been suggested there is a need for careful consideration of current AST use by the CF community. Methods: We engaged a group of experts consisting of pulmonary (adult and pediatric) and infectious disease clinicians, microbiologists, and pharmacists representing a broad international experience. We conducted an iterative systematic survey (Delphi) to determine and quantify consensus regarding key questions facing CF clinicians in the use of respiratory culture results including what tests to order, when to obtain them, and how to act upon the results of the testing. Results: Consensus was reached for many questions but there was not universal agreement to the questions that were addressed. There were some differences with respect to cultures obtained for surveillance compared to when there is clinical worsening. Areas of general consensus include when and how respiratory cultures should be performed, what information should be reported, and when AST should be performed. A key finding is that clinical response to treatment is used to guide treatment decisions rather than AST results. Conclusions: Recommendations are presented regarding questions related to microbiology testing for patients with CF. We have also offered recommendations for priority research questions. © 2019 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Key recommendations • ∗

Corresponding author. E-mail addresses: [email protected] (E. Zemanick), [email protected] (P. Burgel), [email protected] (G. Taccetti), [email protected] (A. Holmes), [email protected] (F. Ratjen), [email protected] (V.J. Waters), [email protected] (S.C. Bell),

Surveillance respiratory cultures should be obtained four times per year

[email protected] (D.R. VanDevanter), fl[email protected] (P.A. Flume).

[email protected]

(J.

Stuart

Elborn),

https://doi.org/10.1016/j.jcf.2019.10.006 1569-1993/© 2019 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Please cite this article as: E. Zemanick, P. Burgel and G. Taccetti et al., Antimicrobial resistance in cystic fibrosis: A Delphi approach to defining best practices, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.10.006

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• •

Respiratory cultures should be obtained at the diagnosis of a pulmonary exacerbation Spontaneously or induced expectorated sputum is preferred for respiratory cultures Respiratory culture results should report both bacterial genus and species Bacterial susceptibility testing should be performed at least once annually, when there is a new pathogen, or at the time of a pulmonary exacerbation Antibiotic selection for treatment is based on bacterial species Changes in antibiotic treatment are based on clinical response to treatment and informed by susceptibility testing

Key research priorities (or opportunities?) •







Which culture data should be used to guide treatment of a pulmonary exacerbation (i.e. how far back should we look?) What is the value of getting a new culture with an exacerbation if there is an existing result within 2–4 weeks? Can we stop suppressive antibiotic therapy if the pathogen ceases to grow in culture? What are the practice patterns related to eradication of pathogens other than P. aeruginosa? What is the optimal timing and use of antimicrobial susceptibility testing?

Methods We used the Delphi method to determine and quantify group consensus [10] implementing a strategy similar to one previously described [11]. The working group consisted of pulmonary (adult and pediatric) and infectious disease clinicians, microbiologists, and pharmacists representing a broad international experience (see acknowledgments). Although all members of the working group were known to the others, the surveys were completed anonymously. A sub-committee (EZ, PRB, GT, AH, FR, CB, PF) developed the surveys and all members of the working group responded using SurveyMonkey. The results of the surveys are expressed using explicit rules that quantify the level of consensus [12]. Delphi surveys The sub-committee organized the surveys around key questions facing CF clinicians in the use of respiratory culture results including what tests to order, when to obtain them, and how to act upon the results of the testing. The questions were developed using different formats including fixed choice, rank order, and to the appropriateness of statements using a Likert scale ranging from 0 (completely disagree) to 10 (completely agree). The participants were allowed to skip statements if they did not have sufficient knowledge or experience to respond. They were also provided opportunity to add comments in support of their opinions or to suggest alternate wording for clarity. Administration of the surveys

Introduction Antimicrobial resistance (AMR) is commonly observed in bacteria cultured from airways of people with cystic fibrosis (CF) [1]. However, the relevance of AMR to treatment decisions is unclear as there is often discordance between microbiologic test results and clinical response to antibiotic treatment. That is, treatment with an antibiotic to which a cultured pathogen is resistant in vitro does not always predict a poor clinical outcome, and conversely, in vitro susceptibility does not ensure a good clinical outcome [2–4]. This discordance is particularly evident in people with CF with chronic Pseudomonas aeruginosa and other non-fermenting Gram-negative bacterial infections [5]. Treatment guidelines for CF recommend antibiotics for a variety of clinical scenarios including eradication of early infection with P. aeruginosa [6], suppressive therapy of chronic airway infection due to P. aeruginosa [6,7], chronic macrolide therapy to reduce exacerbations [7], and intermittent use of antibiotics to treat pulmonary exacerbations (PEx) [8]. While use of antibiotics has contributed to improved clinical outcomes and advances in survival seen in CF, the development of AMR is a serious concern. Given the discordance between laboratory and clinical response, clinicians struggle with the relevance of AMR in people with CF and there is limited guidance on how it should influence antibiotic choices. To deal with these issues, a working group was established to develop guidelines on the definition, interpretation and understanding of AMR for clinical care in CF [9]. As part of this initiative, we developed of a set of recommendations on AMR using a systematic approach to defining consensus. We recognize that there is great interest in antibiotic resistance for fungi and mycobacteria, but we purposefully excluded them from the statements as there is little evidence to base a meaningful discussion. These recommendations for bacterial infection provide some standardization to diagnostic testing and treatment decisions as well as establish key research priorities for the development of appropriate future application of AMR diagnostics to improve patient outcomes.

The internet-based Delphi surveys were submitted to participants who were requested to complete them within two weeks. After the results were analyzed by the sub-committee, the initial survey was refined and resubmitted to the working group. The subsequent iteration of the survey excluded items for which consensus was clear and added elements for clarification. Some items were repeated, accompanied by a summary of the participants’ original responses and a synopsis of their comments. Finally, some items that were determined to be ambiguous were refined. There were two iterations of the surveys overall. Numeric responses to the survey items were summarized and applied to a priori definitions to determine levels of consensus (Supplemental Table 1) [11]. Results Summaries of the final statements put to the committee and the results of their ratings are shown in Tables 1–3 (and Supplemental Tables). When should respiratory cultures be performed? An early lesson in the survey process was that cultures are obtained for different purposes: surveillance for the detection of new pathogens, typically done when patients are in the well state, and diagnostic, performed when patients are more acutely ill (e.g. pulmonary exacerbation, PEx). It was clear that once-annual cultures for surveillance were not considered sufficient (Table 1), scoring strong disagreement (median 0; Good consensus) while the statement that cultures should be obtained more than once per year had high agreement (median 10; Very Good consensus). We asked respondents for the minimum number and ideal number (Supplemental Figures 1 and 2) of cultures required per year to perform proper surveillance. The recommended minimum number of cultures was reported to be 2 (39%) or 4 (42%), with the ideal number being 4 cultures per year (73%) with minor differences when accounting for age (Supplemental Figure 3).

Please cite this article as: E. Zemanick, P. Burgel and G. Taccetti et al., Antimicrobial resistance in cystic fibrosis: A Delphi approach to defining best practices, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.10.006

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Table 1 Survey Results Statements and Panel Ratings.

When should cultures be obtained?

How should cultures be obtained?

Stable surveillance

Exacerbation

What cultures should be reported?



Statements

Median∗

IQR

Consensus

Respiratory cultures should be obtained annually only. Respiratory cultures should be obtained more frequently then annually. Respiratory cultures should be obtained at every encounter. Respiratory cultures should be obtained at clinic visits when the patient is well. Respiratory cultures should be obtained at clinic visits when the patient is ill (i.e. having symptoms of a pulmonary exacerbation). Respiratory cultures should always be obtained after completion of eradication therapy. Respiratory cultures should preferentially be obtained by expectorated sputum.

0 10 6 8 10

0–0.3 10–10 2.8–8 4–10 9.8–10

Good Very Good None Some Very Good

10

10–10

Very Good

10

9–10

Very Good

Respiratory cultures should be obtained by induced sputum if the patient is unable to expectorate sputum (assuming the patient is age appropriate for an induced sputum). Respiratory cultures should be obtained by oropharyngeal swab if the patient is unable to produce sputum. Respiratory cultures should be obtained by bronchoscopy if the patient is unable to produce sputum. Respiratory cultures should preferentially be obtained by expectorated sputum.

6

3–8

None

7

2.5–8

Some

1

0–3

Good

10

9–10

Very Good

8

6.5–9.5

Some

5

2–7.3

None

5

2–6

Some

10

9–10

Good

Respiratory cultures should be obtained by induced sputum if the patient is unable to expectorate sputum (assuming the patient is age appropriate for an induced sputum). Respiratory cultures should be obtained by oropharyngeal swab if the patient is unable to produce sputum. Respiratory cultures should be obtained by bronchoscopy if the patient is unable to produce sputum. Respiratory specimens should be cultured using standard protocols (as noted in infection control guidelines).

Culture methods

Respiratory cultures should be reported by genus and species. Only known CF pathogens should be reported. All cultured bacteria should be reported. Respiratory specimens should be assessed for microbiome. Bacteria identified in respiratory cultures should never undergo susceptibility testing.

10 2 4 2 0

10–10 1.5–5.5 2–8.5 1–4 0–1

Very Good Good None Good Good

Susceptibility testing

Bacteria identified in respiratory cultures should undergo susceptibility testing at least once annually. Bacteria identified in respiratory cultures should always undergo susceptibility testing. Bacteria identified in respiratory cultures should undergo susceptibility testing when culture is obtained at the diagnosis of a pulmonary exacerbation.

10

8–10

Good

2

0.5–6

Some

10

5–10

Good

Scored on a scale of 0 to 10, where 0 represents complete disagreement and 10 represents complete agreement. IQR = interquartile range.

Table 2 How do you use this information? Statements and Panel Ratings. Statements

Median∗

IQR

Consensus

Overall

Bacteria identification results should be used to guide antibiotic choices (i.e. genus and species). Susceptibility results should be used to guide antibiotic choices

10 6

9–10 5–8

Very Good Good

New pathogen

Bacteria identification results should be used to guide antibiotic choices (i.e. do not wait for susceptibility test results). Susceptibility results should be used to guide antibiotic choices (i.e. wait for susceptibility test results). Susceptibility results should be used to change antibiotic choices (i.e. do not wait for repeat culture data but change antibiotics based on susceptibility test results).

8

7–9.5

Good

4

1–7

None

5.5

4–7.5

None

Chronic infection

Bacteria identification results should be used to guide antibiotic choices (i.e. genus and species). Susceptibility results should be used to guide antibiotic choices. Antibiotics for chronic suppressive therapy should be changed (i.e. either stopped or switched to another antibiotic) based on results from recent susceptibility testing.

9 2 2

8–10 1–5.5 1–5.5

Very Good Some Some

Exacerbation

Previous treatment should be used to guide antibiotic choices. Bacterial identification results (i.e. genus and species) should be used to guide antibiotic choices. Susceptibility results should be used to guide antibiotic choices.

8 9 6

7.5–9 8–10 3–8

Good Very Good None



Scored on a scale of 0 to 10, where 0 represents complete disagreement and 10 represents complete agreement. IQR = interquartile range.

There was high agreement and Very Good consensus that patients should have a respiratory culture performed at the time of a PEx (median 10, Table 1). However, we tried to discern whether this was still necessary if a surveillance culture had been performed recently. Although some participants (39%) felt that a culture within 2–4 weeks would suffice, the majority still rec-

ommended a new culture should be performed (Supplemental Figure 4). Finally, we addressed the need for follow-up cultures after an attempt at eradication and there was Very Good consensus for always doing so (median 10, Table 1); this is consistent with guidelines that recommend a subsequent culture should be obtained

Please cite this article as: E. Zemanick, P. Burgel and G. Taccetti et al., Antimicrobial resistance in cystic fibrosis: A Delphi approach to defining best practices, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.10.006

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E. Zemanick, P. Burgel and G. Taccetti et al. / Journal of Cystic Fibrosis xxx (xxxx) xxx Table 3 Antimicrobial treatment choices should be based upon which culture results? Respondents provided how far back to use culture data when making a decision about antibiotic choices. The number of respondents and proportion of entire group are reported. Choices

Number

Proportion

Most recent respiratory culture data Data from all respiratory cultures performed in the last 6 months Data from all respiratory cultures performed in the last 12 months Data from all respiratory cultures performed in the last 24 months

9 10 10 3

28.1% 31.3% 31.3% 9.4%

2–4 weeks after completion of the antibiotics to assess eradication [6,7]. How should respiratory specimens for culture be obtained? Respiratory material may be obtained for culture using nasopharyngeal suctioning, oropharyngeal (OP) swab, expectorated or induced sputum, or bronchoalveolar lavage (BAL). There was high agreement and Very Good consensus that expectorated sputum was the preferred method (median 10, Table 1). We then explored how best to get information when the patient is not able to produce sputum. We asked the participants to rank order the method of obtaining a respiratory specimen (Supplemental Figures 5 and 6). Induced sputum was preferred but OP swabs were acceptable. Bronchoscopy was not a favored choice and was recommended for certain circumstances such as if the patient was deteriorating for unexplained reasons. What should be reported from respiratory cultures? The committee strongly agreed that microbiology laboratories should use standardized CF culture protocols [13] and that both the bacterial genus and species should be reported for isolates (Table 1). They did not feel that current 162-based sequencing methods were appropriate for routine clinical use but required more investigation. As for antibiotic susceptibility testing (AST), there was strong agreement with Good consensus (median 10) that AST be performed at least once annually, but there was disagreement with the statement that AST should always be performed (median 2, Some consensus). We asked whether their responses to these questions were affected by specific bacterial species or by acquisition of a new pathogen (Supplemental Figure 7). In general, the majority favored always performing AST for new bacteria identified by surveillance. There was considerable variation in response for different bacterial species, especially for the less common bacteria (e.g. Stenotrophomonas maltophilia and Achromobacter spp.). There was Good consensus (median 10) that AST be performed when the culture was obtained for a PEx independent of the bacterial species identified (Supplemental Figure 8). How do you use this information? Because bacterial species clearly influenced treatment in all circumstances (Table 1), we sought to understand how AST influenced treatment decisions. For newly identified pathogens, we first needed to know if an eradication treatment plan was used for specific bacterial species. As expected, there was high level of agreement for eradication treatment for P. aeruginosa, but there was considerable variation for other pathogens (Supplemental Figure 9). There was high agreement with Good consensus (median 8) that treatment should not wait on AST results. This was consistent with the relatively low score, but lack of any consensus, on using AST results to influence antibiotic selection.

As for suppressive therapy for chronic infection, AST results also did not appear to influence antibiotic selection (Table 2). We probed this further and found that AST results were rarely used to guide initial antibiotic choices nor did AST results influence a change in antibiotics (Supplemental Figure 10); rather it was a lack of clinical response to treatment that influenced a change in antibiotics which may be guided by AST results. As for the selection of antibiotics for the treatment of a PEx, bacterial species (median 9, Very Good consensus) and previous antibiotic treatment regimen (median 8, Good consensus) had the greatest influence (Table 2). There was no consensus as to the role of AST results in guiding treatment; again it was the clinical response to treatment that had the greatest influence on the decision to change antibiotics (Supplement Figure 11). Which culture result should be used? Since the committee recommended frequent cultures for surveillance and acute illness, we wanted to know which of these results would be used for antibiotic selection. There was a small proportion of respondents (28%) who felt that the most recent culture was the most relevant, while others considered older culture results should be included in treatment decisions (Table 3). Since these could be interpreted differently depending on the circumstances (i.e. chronic suppressive therapy vs. PEx treatment), we asked how much evidence of target pathogen clearance (i.e. culture negativity) would be needed to consider stopping chronic suppressive therapy (Supplement Figures 12 and 13). The threshold for this decision was most commonly selected to be 12 months and/or four negative cultures. Discussion Since airways infection is such an important aspect of CF lung disease, culture of respiratory specimens has become a frequently performed test for monitoring stable patients as well as those experiencing an acute exacerbation. There are no studies that inform us as to the optimal use of such testing, particularly with respect to AST. However, there are observations of a lack of predictive utility of AST [2] and increasing evidence that reduction of AST frequency is not associated with worse outcomes [14]. As there is little evidence to inform best practices, we performed a Delphi survey to establish a consensus of how best to use CF microbiologic testing and to identify potentially relevant research questions that could be tested. Attempts at eradication of first or early P. aeruginosa has become the standard of care [6] and the strategy has been applied to other pathogens [15–18]. As such, a surveillance program has become a necessary component of disease management. While for most patients previous culture results are highly predictive of the next culture result, a survey participant noted that surveillance cultures “rarely reveal a new pathogen but when it does, it changes therapy.” The optimal number of cultures and frequency of testing is not known. Reducing the frequency of cultures could increase the risk of delayed bacterial identification

Please cite this article as: E. Zemanick, P. Burgel and G. Taccetti et al., Antimicrobial resistance in cystic fibrosis: A Delphi approach to defining best practices, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.10.006

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in some patients. There is some evidence of greater success of antimicrobial eradication treatment if initiated earlier [19]. Based on the results of this Delphi, the consensus was that at least four cultures per year should be performed with reporting of the bacterial species of identified pathogens. This recommendation was likely informed by current CFF clinical guidelines recommending quarterly airway cultures [20–23]. It was also recommended to perform a new culture at the time of a PEx. The preferred specimen was an expectorated sputum. If that was not possible, an induced sputum or oropharyngeal swab was considered acceptable, although several respondents noted the challenges of inducing sputum in the clinic. Bronchoscopy was not recommended except for special circumstances such as when patient clinical response does not meet expectations, with respondents noting the invasive nature of this procedure. The development of recommendations regarding interpretation/utilization of AST results is much more problematic. While the committee reported an interest in obtaining AST, especially in the setting of a PEx, the reported utility of AST results appears rather minimal. When we asked about newly identified pathogens, notably, P. aeruginosa and Staphylococcus aureus, the results suggest AST wasn’t needed to initiate antibiotic choices, but with no consensus. The comments suggest respondents are comfortable with initiating treatment without waiting on AST results. Interestingly, the respondents were not keen to change antibiotics based on AST results alone; rather clinical response was an important factor in adjusting antibiotics. As for the selection of antibiotics for chronic infection, there was again little enthusiasm for using AST results in guiding the choice of initial antibiotics or for changing the antibiotics based on AST alone (median 2, Some consensus). In this setting, similar to the treatment of PEx, changes in antibiotics were primarily influenced by the clinical response independent of AST results. Specifically, when asked if AST should be used to change antibiotics irrespective of clinical response, there was low enthusiasm (median 2, Good Consensus). However, for the statement that antibiotics should be changed based on lack of clinical response irrespective of AST results, there was great enthusiasm (median 9, Very Good consensus). Given these results it seems that a reduction in the frequency of AST could be tolerated by clinicians in this setting, with the recognition that they are not using this information in most cases. Indeed, practices that have reduced AST for P. aeruginosa have not noted any apparent adverse outcomes [14]. Antimicrobial eradication treatment is typically a time-limited (e.g. 28 days) course of inhaled antibiotics, while suppressive therapy is used long-term. Treatment for eradication is primarily reported in the pediatric literature, but could be applicable to adults as well. Should patients on suppressive therapy previously considered chronically infected cease culturing the pathogen (e.g. P. aeruginosa) in traditional sputum cultures, it would be reasonable to wonder whether bacterial eradication had been achieved such that the therapy is no longer necessary. There appears to be a willingness to stop therapy after four negative cultures spanning at least 12 months. In conclusion, culture of respiratory tract specimens for surveillance and assessment of acute decline is a standard aspect of CF clinical practice. Clinicians are comfortable in obtaining respiratory cultures by pragmatic measures and are most interested in the identification of bacterial species. Although clinicians value AST results, they do not appear to be a major influence in clinical decision-making; especially in the setting of chronic infection. It is acknowledged that these results are based on the responses of a small working group and may not be consistent with the opinion of the broader community. Some key recommendations and re-

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search priorities identified through the Delphi consensus method are provided (see inset). Declaration of Competing Interest None. Acknowledgments This work was funded by the European Cystic Fibrosis Society, Cystic Fibrosis Foundation, Cystic Fibrosis Trust, Cystic Fibrosis Canada, and Cystic Fibrosis Australia. Dr. Flume’s research time was also supported by the South Carolina Clinical Translational Research (SCTR) Institute, with an academic home at the Medical University of South Carolina, through NIH grant number UL1TR0 0 0 062. We thank our sponsors for this important project including grant support from the Cystic Fibrosis Foundation, the European Cystic Fibrosis Society, CF Canada, CF Australia, and the Cystic Fibrosis Trust (UK). We also thank Christine Dubois for her talents in managing this large group. The following are members of the committee providing experience across disciplines internal and external to CF (∗ steering committee): Europe: Michael Tunney, UK Rafael Canton, Spain Miquel Ekkelenkamp, Netherlands Françoise Van Bambeke, Belgium Pierre–Regis Burgel, France Barbara Kahl, Germany ∗ Stuart Elborn, UK Pavel Drevinek, Czech Republic Giovanni Taccetti, Italy Helle Krogh-Johanssen, Denmark Alison Holmes Anand Shah, UK Alan Smyth, UK USA: ∗ Patrick Flume ∗ Donald VanDevanter Pradeep Singh Kevin Winthrop Marianne Muhlebach Peter Gilligan John Lipuma Susanna McColley Wendy Bullington Lisa Saiman Edith Zemanick Holly Maples Stacey Martiniano Canada: ∗ Valerie Waters Michael Parkins Felix Ratjen Andrew Morris Ranjani Somayaji Australia / New Zealand: Jason Roberts ∗ Scott Bell Tim Kidd Catherine Byrnes Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jcf.2019.10.006.

Please cite this article as: E. Zemanick, P. Burgel and G. Taccetti et al., Antimicrobial resistance in cystic fibrosis: A Delphi approach to defining best practices, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.10.006

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Please cite this article as: E. Zemanick, P. Burgel and G. Taccetti et al., Antimicrobial resistance in cystic fibrosis: A Delphi approach to defining best practices, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.10.006