Finding the relevance of antimicrobial stewardship for cystic fibrosis

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Finding the relevance of antimicrobial stewardship for cystic fibrosis Jonathan D. Cogen a,∗, Barbara C. Kahl b, Holly Maples c, Susanna A McColley d, Jason A. Roberts e,f, Kevin L. Winthrop g, Andrew M. Morris h, Alison Holmes i, Patrick A Flume j, Donald R. VanDevanter k, Valerie Waters l, Marianne S. Muhlebach m, J. Stuart Elborn n, Lisa Saiman o, Scott C Bell p , on behalf of the Antimicrobial Resistance International Working Group in Cystic Fibrosis a

Division of Pulmonary & Sleep Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA Institute of Medical Microbiology, University Hospital Münster, Münster, Germany c Department of Pharmacy Practice, University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock, AR, USA d Division of Pulmonary and Sleep Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, and Northwestern University Feinberg School of Medicine, Chicago, IL, USA e University of Queensland Centre for Clinical Research and School of Pharmacy, The University of Queensland, Departments of Pharmacy and Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Australia f Division of Anaesthesiology, Critical Care, Emergency and Pain Medicine, Nîmes University Hospital, University of Montpelier, Nîmes France g Oregon Health and Science University School of Medicine and Public Health, Portland, Oregon, USA h Division of Infectious Diseases, Department of Medicine, Sinai Health, University Health Network, and University of Toronto, Toronto, Canada i National Institute for Health Research (NIHR) Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, Imperial College London, Hammersmith Campus, London, UK j Medical University of South Carolina, Charleston, SC, USA k Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland OH, USA l Division of Infectious Diseases, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada m Department of Pediatrics, Division Pulmonology, University of North Carolina at Chapel Hill, NC, USA n Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UK o Columbia University Irving Medical Center and New York-Presbyterian Hospital, New York, NY, USA p Department of Thoracic Medicine, The Prince Charles Hospital, and QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia b

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Article history: Received 3 January 2020 Revised 29 January 2020 Accepted 12 February 2020 Available online xxx Keywords: Antimicrobials Antimicrobial stewardship Pulmonary Exacerbations

a b s t r a c t Antimicrobials have undoubtedly improved the lives of people with CF, but important antimicrobialrelated toxicities and the emergence of antimicrobial-resistant bacteria associated with their use must be considered. Antimicrobial stewardship (AMS) is advocated across the spectrum of healthcare to promote the appropriate use of antimicrobials to preserve their current effectiveness and to optimise treatment, and it is clear that AMS strategies are applicable to and can benefit both non-CF and CF populations. This perspective explores the definition and components of an AMS program, the current evidence for AMS, and the reasons why AMS is a challenging concept in the provision of CF care. We also discuss the elements of CF care which align with AMS programs and principles and propose research priorities for AMS in CF. © 2020 Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society.

1. Introduction Antimicrobials have revolutionized the treatment of bacterial infections and saved countless lives, but their improper use is associated with increased healthcare costs, antimicrobial toxicity and antimicrobial-related adverse events, and the global emergence of ∗ Corresponding author at: Seattle Children’s Hospital, 4800 Sand Point Way NE, Seattle, WA, 98105, USA. E-mail address: [email protected] (J.D. Cogen).

antimicrobial-resistant bacteria. These issues have been addressed in part through antimicrobial stewardship (AMS) programs. Even in cystic fibrosis (CF), while antimicrobial use has been associated with dramatic improvement in clinical outcomes, there are growing concerns related to antimicrobial resistance (AMR) [1] and worries about limited antimicrobial benefit that are shared by patients and healthcare providers. Increasingly, the challenge of AMR is being seen through the ‘One Health’ lens by recognizing the interconnections between human health, animals, and the environment. AMS programs have had limited focus on CF to date even

https://doi.org/10.1016/j.jcf.2020.02.012 1569-1993/© 2020 Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society.

Please cite this article as: J.D. Cogen, B.C. Kahl and H. Maples et al., Finding the relevance of antimicrobial stewardship for cystic fibrosis, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2020.02.012

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though antimicrobials are commonly utilized for eradication of newly-acquired respiratory microorganisms, chronic suppression of persistent respiratory microorganisms, and acute (and sometimes repeated) treatment of pulmonary exacerbations (PEx) [2]. Partnerships between AMS and CF care teams could support the optimisation of the benefits of antimicrobial therapies while minimizing unwanted adverse events. Here, we review the potential benefits and challenges of AMS for CF centres and people with CF and discuss specific clinical scenarios as examples of how to optimize AMS. 2. Definition of antimicrobial stewardship For the purpose of this review, AMS refers to guiding the individualized treatment of an infection from defining the need for treatment and its goals to optimising antimicrobial choice(s), dose, and treatment duration to assure the best outcome while reducing the risk for toxicity and side effects. Fundamental aspects to this process are timely and accurate diagnostics identifying the target organism, defining the need for an antimicrobial including dosing frequency and route of administration, the use of a locally-derived antibiogram to guide appropriate empiric antimicrobial treatments, and the dynamic integration of these processes with relevant host factors to enable individualized antimicrobial therapy. Finally, knowledge of relevant clinical trial and dosing data to guide the duration of antimicrobial treatment and the optimal drug dose and mode/route of administration are essential [3-6]. 3. Rationale for antimicrobial stewardship programs AMS programs (at least in the non-CF clinical setting) have grown rapidly in number [7] over the last two decades resulting from evidence supporting their impact on reducing adverse outcomes including the emergence of bacterial resistance, drugrelated toxicity and secondary infections, and reducing healthcare related costs [8]. The United Nations has recognized AMR as a serious threat to its Sustainable Development Goals, and AMS is one of several strategies currently advocated to tackle this issue [9]. Other strategies targeting AMR include enhanced AMR surveillance, infection prevention and control, and research and innovation in diagnostics, vaccines, and novel antimicrobial therapies including phage therapy. 4. Antimicrobial stewardship programs Hospital AMS programs have varied structures depending on the hospital size, patient population, and the resources available (https://www.cdc.gov/antibiotic- use/core- elements/hospital.html). Governance by an AMS committee guides important aspects of the program including committee membership, management reporting responsibilities, and aims of the AMS program. The AMS team should be multidisciplinary including infectious diseases physicians, microbiologists, pharmacists, nursing colleagues, and clinicians (e.g., critical care, oncology, CF). Program activities should be enhanced by contributions from microbiology laboratory staff, infection control practitioners, information technology support staff, patient safety and quality staff, and hospital epidemiologists and health economists [6,10,11]. The potential roles of team members are described in Fig. 1. AMS programs can influence prescriber behavior using approaches which are enabling or may be restrictive or a combination of both. Enabling approaches preserve prescriber autonomy and use behavior change techniques such as “nudging”, normative feedback, and peer-to peer comparison to foster self-reflection on ‘best practice’, including the role of antimicrobials in a specific clinical situation [12]. Restrictive approaches include limiting

access to certain antimicrobials that require consultation to start (pre-approval) or continue restricted antimicrobials. The relative merits and sustainability of each approach continue to be evaluated [13-15]. AMS programs are enhanced when there are active linkages to safety and quality units, drug and therapeutic committees, regulatory agencies, and clinical governance processes within the institution, and are also transparent in the involvement of patients and the public. Determining whether AMS programs are achieving their objectives is important by using process and outcome indicators, such as how often therapeutic drug monitoring (TDM) occurs during in-hospital PEx treatment with aminoglycosides. 5. Why is AMS challenging in CF? Antimicrobials have played an enormous role in the improved outcomes of people with CF over the last several decades, and are recommended for eradication protocols [16-18], suppression of persistent respiratory microorganisms, and acute PEx treatment [2]. Antimicrobials are frequently given to children with CF for persistent cough even when respiratory viruses have been identified or presumed (Panel 1). Registry analyses have found that CF clinics whose patients have better lung function (measured as percent predicted average forced expiratory volume in 1 s (ppFEV1 )) used more intravenous (IV) antimicrobials, had more inpatient days of treatment, and had more frequent lung function and respiratory culture monitoring than centres whose patients had lower lung function [19]. In addition, a more contemporary study showed that top quartile centres initiate antimicrobials more frequently for symptoms of PEx [20]. Antimicrobials are extensively utilized to treat PEx in both the inpatient and the outpatient setting, even though there are a lack of evidence-based guidelines for PEx treatment. In addition, there is a well-described discordance between clinical outcomes and antimicrobial susceptibility test results [21]. For example, in a national observational study from Australia, multidrug resistant Pseudomonas aeruginosa (P. aeruginosa) strains in children and adults with CF were associated with IV antimicrobial intensity in children but not with worse clinical outcomes [22]. Thus, clinicians caring for people with CF may be reluctant to reduce antimicrobial use by integrating with AMS programs and are fearful that this could result in adverse outcomes for people with CF. Alternatively, CF clinicians may welcome the support of AMS programs in the choice of less toxic or less expensive antimicrobials when indicated for individualized treatment. As described below, many of the activities of AMS programs are broader than restricting antimicrobials and are highly relevant to CF care. 5.1. Use of respiratory cultures for microorganism surveillance There are a number of challenges to the implementation of AMS programs in CF (Table 1), the first of which is related to respiratory microorganism detection. There are several methods of respiratory culture acquisition including oropharyngeal or ‘cough’ swabs, induced or spontaneously produced sputum, and bronchoalveolar lavage (BAL) [23-28]. There are recommended CF-specific respiratory culture protocols to increase the ability to identify relevant microorganisms [29,30], but centres with limited CF experience may be unfamiliar with these methods, which may lead to underdetection of respiratory microorganisms. When microorganisms are detected it is unclear if antimicrobial treatment is always needed to improve clinical signs and symptoms. The CF airways are frequently colonized or infected with multiple respiratory microorganisms (e.g., bacteria, viruses, and fungi), making antimicrobial selection challenging. Importantly, there are well recognized limitations of upper airway sampling in terms of diagnostic accuracy,

Please cite this article as: J.D. Cogen, B.C. Kahl and H. Maples et al., Finding the relevance of antimicrobial stewardship for cystic fibrosis, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2020.02.012

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Fig. 1. Possible Antimicrobial Stewardship Team Member Roles.

further adding to the challenge of antimicrobial choice [23-28,31]. Similarly, the role of BAL-directed cultures to support clinical decision making has not been established in clinical practice [32]. 5.2. Antimicrobial pharmacokinetics and pharmacodynamics A second challenge to optimal antimicrobial use in CF is related to antimicrobial pharmacokinetics and pharmacodynamics. People with CF are commonly undernourished and have less adipose tissue compared to the general population, and thus the volume of distribution (Vd ) may be increased in CF, leading to different systemic antimicrobial prescribing requirements (increased dose or frequency) [33]. People with CF have rapid clearance of renally-excreted antimicrobials, and thus may require higher-thanusual doses to achieve therapeutic serum concentrations [34]. Antimicrobial dosing often needs to be adjusted during a hospitalization after clinical improvement is seen (lower Vd ) to avoid toxicity. Consequently, TDM is recommended, particularly for aminoglycosides and glycopeptide drugs (e.g., vancomycin and teicoplanin). A randomized controlled trial demonstrated equal efficacy for IV tobramycin if given once versus three times daily in the treatment of an acute PEx [35], and current PEx guidelines conclude that oncedaily aminoglycoside dosing is acceptable for P. aeruginosa treatment [36]. For beta-lactam antimicrobials, the dosing is more complex as well-validated and usable assays for TDM are less available. Beta-lactam pharmacokinetic and pharmacodynamic profiles suggest that continuous infusion may be useful to optimise efficacy, but there are limited data on clinical effectiveness in people with CF [37]. Finally, some medications (e.g., azoles) pose drug-drug interaction concerns that often require TDM and dose adjustment to prevent medication toxicity [38]. 5.3. Antimicrobial resistance Antimicrobial susceptibility testing (AST) is used to detect AMR among CF respiratory microorganisms; however, the clinical utility

of AST results in CF is limited, particularly for people with chronic P. aeruginosa infection [1,39]. A recent systematic review of AST in CF found that among twenty separate studies, little evidence existed that AST predicted clinical outcomes of CF antimicrobial treatment [21]. An expert panel of pulmonary and infectious disease clinicians, microbiologists, and pharmacists representing broad international experience was recently convened to determine and quantify consensus on how best to utilize AST. The key recommendations [40] were: (a) Surveillance respiratory cultures should be obtained four times per year; (b) Respiratory cultures should be obtained at PEx diagnosis; (c) Spontaneously or induced expectorated sputum is preferred for respiratory cultures; (d) Respiratory culture results should report both bacterial genus and species; (e) Bacterial susceptibility testing should be performed at least once annually, when there is a new microorganism, or at time of a PEx; (f) Antimicrobial selection for treatment is based on bacterial species; (g) Changes in antimicrobial treatment are based on clinical response to treatment and informed by AST (Panel 2). Additional studies are needed to incorporate these new data into updated PEx guidelines [2,36,41] and to determine how best to utilize AST in CF clinical care. With respect to AST, since susceptibility results do not appear important in predicting response to antimicrobial therapy [21], they may instead serve as a marker of more severe disease or of earlier antimicrobial exposure. Nevertheless, the CF community is becoming progressively concerned about increasing rates of antimicrobial resistance. Exposure to antimicrobials selects for resistance through a variety of mechanisms [42]. For example, the drug efflux pump MexAB-OprM when up-regulated can remove beta-lactams, fluoroquinolones, macrolides, and sulfonamides from P. aeruginosa, rendering the antimicrobials less effective [43]. P. aeruginosa carries an inducible AmpC cephalosporinase that can be overproduced in the setting of antimicrobial treatment leading to antimicrobial resistance to all beta-lactams (with the exception of carbapenems) [44,45]. In addition, point mutations in the pmrB protein are known to contribute to high-level polymyxin resistance

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Table 1 Antimicrobial stewardship challenges in CF. Challenge Empiric treatment of suspected but undocumented CF-specific microorganisms

Origins

Impact

• Reliance on low-sensitivity and low-specificity

• • • •

oropharyngeal cultures or “cough swabs” in non-expectorating patients Prescription after phone or primary care encounter without new culture Difficult to evaluate for adapted phenotypes of slow-growing microorganisms (e.g., BCC, NTM, etc.) Viral infection-related PEx Epidemiology showing better pulmonary function outcomes with increased antimicrobial treatment

Challenges to adequate respiratory culture collection

• Feasibility and reliability of induced sputum

Utilization of suppressive continuous or cycled antimicrobials

• Optimal approach to P. aeruginosa suppression (daily,

Treatment of patients with PEx

Polymicrobial infection

collection in ambulatory practice in non-expectorating people with CF • Lack of access to CF-specific respiratory microbiological culture protocols outside of CF centres and their specialized and experienced laboratories or due to insurance coverage • Delays in receiving contemporary respiratory culture results including antimicrobial susceptibility testing (typically takes 5-7 days to result) • Cost and scheduling of bronchoscopy in more difficult-to-treat cases

intermittent, or cycling of antimicrobials) • Efficacy of continuous intermittent inhaled antimicrobials for P. aeruginosa on short and longer-term clinical outcomes • Continuous use of anti-staphylococcal antimicrobial therapy to suppress MSSA in some countries/CF centres • Various strategies to suppress less common organisms (e.g., Stenotrophomonas maltophilia, Achromobacter xylosoxidans)

adaptive phenotypes (SCVs, mucoid isolates, and persister cells) in previously-identified respiratory microorganisms • Emergence of newly identified treatment-emergent bacteria • Short-term adverse reactions: allergic and immunological • Long-term adverse reactions: nephrotoxicity and ototoxicity • Respiratory culture data are absent or

delayed

• Growth of treatment-emergent resistant

bacteria • Growth of adaptive phenotypes, persister

cells • Induction of resistance • Earlier growth of P. aeruginosa • When to stop suppressive therapy

• Lack of a standardized PEx definition • Absence of evidence-based guidelines identifying

• Growth of treatment-emergent infections • Induction of AMR

optimal treatment duration, antimicrobial selection, or antimicrobial route of administration (i.e., IV, oral, or inhaled) • Increased exposure to antimicrobials • Increased visits to health care facilities

• Healthcare-associated infections

• Treatment with multiple antimicrobials and

• Drug-drug interactions • Induction of resistance

antimicrobial classes • Discordance between culture and antimicrobial susceptibility results and clinical outcomes Chronic infection

• Induction of resistance and growth of

• Bacterial adaptation (e.g., mucoid phenotypes, SCVs,

• Adverse drug reactions

• Suppression of bacterial density

persister cells, etc.)

in clinical isolates of P. aeruginosa [46]. Some CF microorganisms have shown development of persister cells in vitro—dormant phenotypic variants in which antimicrobials are largely inactive—and have been linked with chronic infection and treatment failure [47]. Small-colony variants (SCVs) of Staphylococcus aureus (S. aureus) are selected for in vitro by long-term exposure to certain antimicrobials (e.g., trimethoprim-sulfamethoxazole) and may confer resistance to other antimicrobials, including aminoglycosides [48-50]. These SCVs are independently associated with worse respiratory outcomes in children with CF [49,51,52]. The use of both empiric and targeted antimicrobial therapy is associated with the emergence of treatment-resistant bacteria and with growth of bacteria that are intrinsically resistant to a given antimicrobial. A Cochrane review evaluating antimicrobial prophylaxis against S. aureus in CF infants found a trend towards a higher P. aeruginosa endobronchial colonization prevalence by age four years [53], although no conclusions were drawn about the long-term effects. CF START, a national U.K. trial randomizing infants to flucloxacillin or placebo at birth through 2 years of age,

is currently underway to more definitively determine whether prophylaxis against S. aureus results in improved health outcomes or leads to earlier P. aeruginosa acquisition [54]. AMR and the emergence of new antimicrobial-resistant organisms were well-described in studies evaluating tobramycin inhalation solution (TIS) for chronic P. aeruginosa infection, in which Aspergillus fumigatus increased in frequency in participants randomized to the active drug compared to participants taking placebo [55-57]. Whether this observation is related to selection of these highly antimicrobial-resistant species in CF airways and/or increased detection of microorganisms already present in the lung with suppression or eradication of other bacteria is unknown. 5.4. Risks/Consequences of antimicrobial use There are well-described short- and long-term risks to antimicrobial administration that affect people with CF. A distinction between toxicity and intolerance to antimicrobials can be challenging particularly if documentation is historical. The majority of

Please cite this article as: J.D. Cogen, B.C. Kahl and H. Maples et al., Finding the relevance of antimicrobial stewardship for cystic fibrosis, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2020.02.012

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Table 2 Antimicrobial stewardship opportunities in CF. Challenge

Examples

Best practices for the treatment of PEx

• Identification of causative microogranism(s) • Initiation of therapy (who should be treated with

antimicrobials) • Route of therapy (systemic versus topical) • Number of antimicrobials (spectrum of coverage) • Duration of therapy • Location of therapy (in-hospital vs outpatient) • Defined treatment goal/How to monitor treatment

response • Limiting excessive antimicrobial therapy • Greater emphasis on minimising

antimicrobial-related toxicity Appropriate assessment of drug allergies

• Drug-allergy (and intolerance) assessed by healthcare

provider (rather than parental or patient report) and recorded in the clinical chart Management of antimicrobial intolerance

• Nausea associated with antimicrobial therapy • Bone-marrow suppression • Drug fever • Pruritis • Diarrhea (non-infectious)

Vigilance/management of toxicity

• Acute kidney injury • Ototoxicity • Hepatitis • C. difficile infection

short-term toxicities are allergic/immunologic, which range from mild to life-threatening, and include rash, nausea and vomiting, diarrhea, liver enzyme elevation, bone-marrow suppression, and Clostridioides difficile (C. difficile)-associated pseudomembranous enterocolitis (Panel 3). The challenges related to documenting, verifying [58], and recording antimicrobial drug allergies versus intolerance in the clinical setting may contribute to the difficulty of determining specifics of any reactions that have occurred and whether to avoid use of the agent in the future. Acute and chronic kidney injury, ototoxicity, and vestibular toxicity are serious adverse outcomes that are often seen in people with CF exposed to aminoglycosides [59]. 6. Elements of CF care which align with AMS programs/principles Effective CF AMS programs should also carefully integrate the evidence from epidemiologic studies and clinical trials on the significant benefits of antimicrobial use in CF to develop behavioral change approaches and facilitate the optimal use of antimicrobial therapies, balancing the clinical benefit with the least potential for toxicity and development of AMR. The AMS principle most studied in CF relates to optimising antimicrobial dosing, with particular emphasis placed on aminoglycoside dosing regimens. Other studies have evaluated the benefit of establishing treatment algorithms for appropriate aminoglycoside dosing and toxicity monitoring [60] (Panel 4). The Standardized Treatment of Pulmonary Exacerbations (STOP-II) study is currently enrolling people with CF experiencing PEx into a randomized controlled trial that aims to determine the optimal duration of IV antimicrobial therapy [61]. Nevertheless, currently insufficient evidence exists to define other important PEx treatment strategies, such as the simultaneous use of IV and inhaled antimicrobials or the number of antimicrobials used for PEx treatment [36]. Examples of AMS opportunities in CF are summarized in Table 2. Current practices in CF treatment support much of the necessary infrastructure for collaborations with AMS stewards and

the insertion of AMS programs and principles into CF clinical care. CF centres, in collaboration with clinical microbiology laboratories, are charged with ensuring that appropriate standards for processing respiratory tract specimens for microorganism detection exist. This process allows for detection of respiratory microorganisms and supports the surveillance of AMR patterns among CF respiratory microorganisms. In addition, partnerships may exist between CF clinical care teams and infectious disease clinicians who often can assist with antimicrobial selection for acute PEx treatment (though it is unclear how frequently this occurs in practice), especially in the treatment of challenging infections (e.g., Burkholderia cepacia complex (BCC) species or non-tuberculous mycobacteria (NTM)). Many pediatric and adult CF care centres have incorporated CF-specific pharmacists into their clinical teams who provide antimicrobial dosing and TDM recommendations. Critical components to AMS programs include collection of data to guide AMS team recommendations, the development of treatment algorithms, and monitoring adherence to recommendations. Fortunately, in CF much of this data-gathering infrastructure is already in place. CF-specific data registries including those from North America, Europe, and Australia provide CF researchers with an opportunity to leverage existing data in a cost-effective manner to describe antimicrobial regimens, to evaluate interventions, and to look for trends in outcomes and practice patterns. For example, the U.S. CF Foundation Patient Registry (CFFPR) was recently linked with a large pediatric inpatient database that captures inhospital antimicrobial data [62] (e.g., antimicrobial dose, route, number of hospital days prescribed) allowing for comparative effectiveness studies evaluating antimicrobial use for PEx treatment. Infrastructure exists to support quality improvement projects at the local and regional level. The CF Learning Network was launched by the CF Foundation in 2016 to address clinical care outcomes and quality of life and reduce cost of care [63]. Thus, the existence of data repositories and quality improvement collaborations align with AMS principles and can facilitate the integration of AMS into CF clinical care.

Please cite this article as: J.D. Cogen, B.C. Kahl and H. Maples et al., Finding the relevance of antimicrobial stewardship for cystic fibrosis, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2020.02.012

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7. Antimicrobial stewardship opportunities for CF Frameworks for AMS exist in hospitals and health services and yet most CF clinical services have had few formal interactions with AMS programs. The lack of engagement may relate to concerns of CF clinicians related to the restriction of antimicrobials as well as the limited exposure by AMS stewards to CF care in the current era. There are good reasons to develop this collaborative relationship. AMS programs have been successfully working with subspecialty services in which the use of empirical antimicrobial therapy is common, such as haematology, transplantation services, and critical care [64-66]. As outlined previously, many of the elements of an effective AMS program are already a part of care of the person with CF. These elements include guidelines for treatment of PEx, close relationships with clinical microbiology services and infection prevention and control teams, and the inclusion of pharmacists and nurses as core members of the CF multidisciplinary team who contribute to monitoring of drug therapy including TDM and the assessment of drug allergies. Recent surveys have highlighted that antimicrobial use (and overuse) are important to people with CF and their families. Respondents in the U.K., including people with CF, parents of a person with CF, and friends and families, indicated that five of their ten research priorities were related to the use of antimicrobial therapy [67]. These included (1) simplifying the treatment burden of people with CF, (2) identifying the best treatment for NTM infection, (3) determining the optimal antimicrobial combinations and dosing plans for PEx, (4) reducing antimicrobial adverse effects, and (5) identifying the best P. aeruginosa eradication protocols.

6 Combined multidisciplinary team meetings to discuss cases and the results of continuous auditing (e.g., 4a. and 4b.) and interval auditing (e.g., 4c. and 4d.) 8. Research priorities for AMS and CF The role and impact of AMS is a fertile area for research. It is essential to understand if certain attitudes and practice barriers may impede AMS implementation by CF providers and their care teams. Research is needed on how best to incorporate AMS process measures into CF clinical care to ensure that the implementation of AMS strategies aimed at reducing adverse drug events, excessive antimicrobial utilization, and costs do not negatively affect clinical outcomes. Additional research priorities include evaluation of how AMS implementation affects the acquisition of antimicrobialresistant organisms in CF as well as enhanced personalized dosing and therapeutic drug monitoring of host factors and microbiology diagnostics. The CF research community should prioritize knowledge gaps on the treatment of lung infections. These gaps include identifying what aspects of microbiologic testing help to best inform treatment decisions (e.g., how best to obtain reliable lower respiratory specimens in non-expectorating people with CF) or developing novel methods to improve treatment. Finally, and perhaps most importantly, work is needed on how best to engage the CF community and people with CF in addressing the optimal use of antimicrobials and AMR in CF. Ultimately evidence-based treatment guidelines for the treatment of CF pulmonary disease should consider AMS principles. 9. Panel 1—Case 1: Viral-induced PEx

7.1. How to start communication between the CF and AMS teams? Engagement and communication between CF and AMS teams (as well as engagement and involvement from people with CF and their families) are important to build long-standing collaborations and improve antimicrobial utilization for people with CF. We suggest the following strategies: 1 Enhancing relationships and regular engagement between the CF clinical and AMS teams would be an important first step. 2 Education for AMS Team: to support better understanding of the current use of antimicrobial therapies and impact on CF outcomes. 3 Education of CF Team: to enhance understanding of the purpose and benefits of AMS in general, and how these may translate to the care of the person with CF. 4 Education of people with CF and their families: to ensure patient and family-level understanding and engagement in the benefits of AMS. 5 Consider opportunities for auditing antimicrobial use involving the CF and AMS teams and microbiologists. a Determine availability of resources and establish goals for this collaboration. b Review current guidelines for antimicrobial therapy in people with CF. c Monitoring for aminoglycoside and glycopeptide toxicity including effective use of TDM in the CF centre population, with specific guidance from CF pharmacists. d Monitoring rates of multidrug resistance and the acquisition of antimicrobial resistance within important CF bacteria. e Assessing for rates of drug intolerances, allergies, and hypersensitivity and their documentation in the medical record. f Managing acute respiratory viral infections and the role and utilization of antimicrobials.

A 5-month-old girl diagnosed with CF via newborn screening was growing well and had no respiratory symptoms. Her treatment included pancreatic enzymes, oral salt replacement, and chest physiotherapy in accordance with clinical care guidelines; she was not on long-term anti-staphylococcal therapy. Her previous oropharyngeal cultures, last obtained 2 weeks prior to admission, had grown either normal respiratory flora or MSSA on different cultures. She presented to CF clinic with 3 days of rhinorrhea, cough, pallor, and visible respiratory distress. Her SpO2 was 94% in room air. On examination, she was pale with nasal flaring and visible inspiratory intercostal contractions, fine crackles throughout her lung fields, and mild expiratory wheezes. She was admitted to the hospital and a respiratory-PCR nasopharyngeal swab was positive for respiratory syncytial virus (RSV). IV fluids and frequent chest physiotherapy were prescribed. Her care team debated if she should receive antimicrobials, treating MSSA endobronchial infection and/or possible other organisms not previously identified; the care team opted for ‘watchful waiting’ and antimicrobials were not prescribed. Her symptoms improved over 3 days, at which time she was discharged on her usual therapies along with an increased frequency of chest physiotherapy. 9.1. Discussion Viral lower respiratory tract infections are common in young children and are associated with PEx in infants and young children with CF. Children with CF shed virus in the upper respiratory tract for a longer period of time compared to healthy peers, and rhinovirus infections have been associated with poor recovery after PEx [68,69]. Viral infection may increase the pathogenicity of bacteria in the lower respiratory tract [70] even while bacterial sputum density does not increase [71,72]. Furthermore, the incidence of viral identification is common in children during PEx,

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and is associated with worse symptom severity [69,73]. These reasons might support antimicrobials for PEx symptoms in infants and young children with CF, even when a respiratory viral infection is documented. Careful observation of a mildly unwell child may allow resolution of symptoms without requiring antimicrobial treatment. In the setting of PEx in which viral infection is present, more research is needed on whether antimicrobial treatment is associated with improved lung function outcomes later in life.

not illustrated improved outcomes compared to studies that rely on more conventional respiratory culture techniques [76]. The dynamics of antimicrobial response in CF is complex, particularly as there is phenotypic heterogeneity of airway pathogens [77,78]. In addition, since respiratory cultures are obtained over time for microorganism surveillance and acute illness, further study is needed to determine relevant timing for respiratory culture collection to guide clinical management.

10. Panel 2—Case 2: What role exists for antimicrobial susceptibility testing?

11. Panel 3—Case 3: Case of Clostridioides difficile-associated pseudomembranous enterocolitis

A 27-year-old female with CF was admitted to the hospital for a PEx characterized by increased cough, poor appetite, weight loss, and a 10% absolute decrease in ppFEV1 . She had a history of P. aeruginosa isolation from prior sputum cultures, most recently 3 months ago, and her last treatment for a PEx was one year ago when she was treated with IV piperacillin-tazobactam and IV tobramycin. She was treated again with IV piperacillintazobactam and IV tobramycin as well as usual care consisting of airway clearance therapies, her chronic medications (dornase alfa, thrice weekly azithromycin, salbutamol, and nebulized hypertonic saline), and nutritional supplementation. On admission, a sputum sample was collected for culture. After one week of treatment she reported marked improvement in her symptoms with reduced cough and the sputum was described as less purulent. Spirometry demonstrated an 8% improvement in ppFEV1 (within 2% of her prior baseline). Her admission sputum culture identified P. aeruginosa and AST illustrated resistance to piperacillin-tazobactam and ceftazidime, but sensitive to meropenem. Rather than replacing IV piperacillin-tazobactam with IV meropenem based on susceptibility results, the team elected to continue current IV antimicrobial therapy. She completed a twoweek course of antimicrobials at home (after one week in hospital) and in clinic one month later her ppFEV1 was unchanged from discharge.

A 25-year-old man with CF (F508del/ N1303K), pancreatic insufficiency, CF-related diabetes, and chronic P. aeruginosa endobronchial infection presented to his routine outpatient CF clinic visit complaining of increased sputum production, increased cough, and worsening fatigue. He was diagnosed with a PEx and was started on a 21-day course of oral ciprofloxacin. One week following the completion of ciprofloxacin, he presented to the emergency room complaining of acute abdominal pain, nausea, vomiting, and hematochezia. He was admitted for IV fluids and further evaluation; an abdominal x-ray showed non-specific findings without evidence of stool retention or fluid levels. He underwent a colonoscopy that revealed the presence of diffuse pseudomembranous colitis and a stool toxin polymerase chain reaction (PCR) confirmed the presence of C. difficile. He was treated with oral vancomycin and IV metronidazole for C. difficile enterocolitis, and ultimately discharged home. Over the next several years, he continued to have intermittent episodes of abdominal pain and haematochezia following antimicrobial administration that was treated with oral vancomycin treatment.

10.1. Discussion This case demonstrates a reasonably common finding and treatment decision in PEx management when there may be a discordance between clinical outcomes and what might have been predicted by AST. In this case, the P. aeruginosa identified on hospital admission was resistant based on in vitro testing to the antimicrobials prescribed yet the patient clinically improved. The value of AST in CF has come under question [21]; recently, a Delphi survey was conducted among CF experts and it is apparent that clinical response to treatment is more important to clinicians than AST data obtained from respiratory cultures [40]. Furthermore, since the emergence of carbapenem resistance in P. aeruginosa and other bacteria in both CF and non-CF populations [74,75], in this instance an argument could be made to continue a more narrowspectrum antimicrobial like IV piperacillin-tazobactam or IV ceftazidime rather than replacing with IV meropenem to try and preserve meropenem’s future activity. There are many relevant questions that need to be addressed related to antimicrobial selection, including data on optimal antimicrobial dosing strategies and treatment duration. The selection of antimicrobials is often guided by respiratory culture results that identify a particular microorganism and its antimicrobial susceptibility data. Microbiome studies have illustrated the microbial complexity in the airways of people with CF that makes it challenging for treating clinicians to know what microorganism should be targeted, and whether information related to treatment is available from standard respiratory cultures. Interestingly, initial studies using microbiome test results to guide PEx treatment have

11.1. Discussion C. difficile-associated pseudomembranous enterocolitis is a wellrecognized complication of antimicrobial use [79]. Early studies evaluating C. difficile in people with CF noted a higher asymptomatic carriage rate [80]. More recently, studies have described several risk factors associated with the development of C. difficile enterocolitis in people with CF, including recent antimicrobial use [81], presence of the N1303K mutation [82], and lung transplantation [83,84]. Infectious Disease Society of America treatment guidelines for adults recommend oral vancomycin over metronidazole for an initial episode of C.difficile enterocolitis [85]. This case highlights frequent challenges related to treating PEx including the selection of specific agents for PEx treatment (in this case in the outpatient setting) and the duration of antimicrobial therapy; could this complication have been prevented with use of an alternative antimicrobial (difficult because there are limited oral agents for P. aeruginosa), a shorter duration, or addition of an agent to reduce the risk of C difficile enterocolitis (e.g., probiotics)? 12. Panel 4—Case 4: Case of aminoglycoside toxicity A 7-year-old girl was admitted to the hospital for a PEx characterized by increased cough, chest pain, weight loss, and new crackles in her right lower lobe on chest auscultation. She had a history of P. aeruginosa isolation from an oropharyngeal swab 18 months prior to admission. At that time, she was treated as an outpatient with a 4-week course of TIS, and subsequent cultures were negative. She had been previously treated in-hospital two months prior to this current admission for a PEx with IV ceftazidime and IV tobramycin. During this previous hospital stay, no microorganisms were isolated from an oropharyngeal cough swab culture prior to initiation of therapy; due to a recent history of P. aeruginosa infection, tobramycin was administered at a dose of 10 mg/kg every 24

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hours and pharmacokinetic studies following two doses showed a peak level of 24 mcg/ml and a trough level of 0.6 mcg/ml. During this current hospital stay, she underwent flexible fiberoptic bronchoscopy with bronchoalveolar lavage (BAL). She was empirically started on IV ceftazidime and IV tobramycin (same doses as her prior admission), and P. aeruginosa was isolated from the BAL specimen on day 3 of the admission. She was given a nonsteroid anti-inflammatory agent (NSAID) daily for her chest pain, and over the next several days her signs, symptoms, and spirometry improved. Tobramycin pharmacokinetics were not performed due to established levels at the recent prior admission. Creatinine was monitored weekly and was 0.4-0.5 mg/dl (normal range). On hospital day 10, TIS twice daily was started in combination with IV antimicrobials, with the intent to continue TIS following discharge. On hospital day 14, IV antimicrobials were discontinued, and she was discharged home with TIS and NSAIDs to be used as needed for pain. Three days later she had vomiting and fatigue which worsened over the next four days. She was seen in the emergency department with the following labs: blood urea nitrogen 60 mg/dl and a creatinine 5.2 mg/dl. She was admitted for IV fluids and dialysis; TIS and NSAIDs were discontinued. Her creatinine improved but did not return to established baseline. A thorough review of the drug administration record did not reveal an error in tobramycin dosing or timing of administration. 12.1. Discussion This case highlights challenges related to the dosing of aminoglycoside antimicrobials and their concomitant use with other potentially nephrotoxic medications. Aminoglycoside antimicrobial use has been associated with acute and longer term-kidney injury, hearing loss, and vestibular toxicity [86-89]. Dosing of these antimicrobials can become difficult as their Vd may change over the course of the hospitalization, and for this reason, frequent therapeutic drug monitoring is recommended. With respect to concomitant inhaled and IV antimicrobial use, an early inhaled tobramycin pharmacokinetic study in people with CF illustrated high airway drug concentrations with relatively low serum concentrations [90], indicating minimal systemic inhaled antimicrobial absorption. However, a recent Cochrane review noted insufficient evidence to recommend the use of inhaled antimicrobials for PEx treatment [91]. Additionally, co-administration of acute therapies for symptom relief and long-term agents may have nephrotoxic (e.g., NSAIDs) or ototoxic (e.g., azithromycin) impact independently or cumulatively with aminoglycosides, particularly in the setting of dehydration. Alternative pain relief to NSAIDs should ideally be considered. The use of IV fluids (including normal saline boluses prior to daily aminoglycoside dosing) and medication reconciliation (in conjunction with a clinical pharmacist) are likely important to minimize the risk of drug-related adverse outcomes. 13. Antimicrobial resistance international working group in cystic fibrosis Europe: Michael Tunney, UK, pharmacy Rafael Canton, Spain, microbiology Miquel Ekkelenkamp, Netherlands, microbiology Françoise Van Bambeke, Belgium, microbiology Pierre–Regis Burgel, France, adult pulmonary Barbara Kahl, Germany, microbiology ∗ Stuart Elborn, UK, adult pulmonary Pavel Drevinek, Czech Republic, microbiology Giovanni Taccetti, Italy, pediatric pulmonary

Helle Krogh-Johanssen, Denmark, microbiology Alison Holmes, adult infectious diseases Anand Shah, UK, adult pulmonary Alan Smyth, UK, pediatric pulmonary USA: ∗ Patrick Flume, adult pulmonary ∗ Donald VanDevanter, microbiology and epidemiology Kevin Winthrop, adult infectious diseases ∗ Marianne Muhlebach, pediatric pulmonary Peter Gilligan, microbiology John Lipuma, pediatric infectious diseases Susanna McColley, pediatric pulmonary Wendy Bullington, pharmacy ∗ Lisa Saiman, pediatric infectious disease Edith Zemanick, pediatric pulmonary Holly Maples, pharmacy and AMS Stacey Martiniano, pediatric pulmonary Jonathan Cogen, pediatric pulmonary Canada: ∗ Valerie Waters, pediatric infectious disease Michael Parkins, adult infectious disease Felix Ratjen, pediatric pulmonary Andrew Morris, adult infectious diseases and AMR Ranjani Somayaji, adult infectious disease Australia / New Zealand: Jason Roberts, pharmacist ∗ Scott Bell, adult pulmonary Tim Kidd, microbiology Catherine Byrnes, pediatric ∗ Steering Committee Funding This work was funded by the European Cystic Fibrosis Society, Cystic Fibrosis Foundation, Cystic Fibrosis Trust, Cystic Fibrosis Canada, and Cystic Fibrosis Australia. Jonathan Cogen has funding from the CF Foundation (USA). Susanna McColley is supported, in part, by the National Center for Advancing Translational Sciences of the National Institutes of Health under Grant Number UL1TR001422. Jason Roberts has funding from the Australian National Health and Medical Research Council for Centre of Research Excellence and Practitioner Fellowship. Alison Holmes is a National Institute for Health Research (NIHR) Senior Investigator. She also acknowledges the support of the NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at Imperial College London. Patrick Flume is supported, in part, by the National Center for Advancing Translational Sciences of the National Institutes of Health under Grant Number UL1TR001450. J. Stuart Elborn receives funding from the Innovative Medicines Initiative, Framework Seven, European Commission and from the Medical Research Council, UK. Lisa Saiman receives funding from the CF Foundation (USA). Scott Bell has funding from Australian National Health and Medical Research Council, the CF Foundation (USA) and the Queensland Children’s Foundation. Declaration of Competing Interest Drs. Kahl, Maples, Holmes and Muhlebach have nothing to disclose. Dr. Cogen reports grants from the Cystic Fibrosis Foundation outside of this work. Dr. McColley reports disclosures from Vertex Pharmaceuticals, Gilead Sciences, and grants from Northwestern University Clinical and Translational Sciences Institute outside of this work. Dr. Roberts reports grants and personal fees from MSD, grants from QPEX, personal fees from Discuva, personal fees from Accelerate Diagnostics, grants and personal fees from

Please cite this article as: J.D. Cogen, B.C. Kahl and H. Maples et al., Finding the relevance of antimicrobial stewardship for cystic fibrosis, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2020.02.012

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Biomerieux, grants and personal fees from Pfizer and grants from The Medicines Company outside of this work. Dr. Winthrop reports grants and personal fees from Pfizer, personal fees from AbbVie, personal fees from UCB, personal fees from Lilly, personal fees from Galapagos, personal fees from GSK, personal fees from Roche, personal fees from Gilead, grants from BMS, and grants from Insmed outside of this work. Dr. Morris reports and receives salary support from the Sinai Health and University Health Network in his role as Director of their Antimicrobial Stewardship Program. Dr. Flume reports grants outside of this submitted work from the European Cystic Fibrosis Society, the Cystic Fibrosis Foundation, Cystic Fibrosis Trust, Cystic Fibrosis Canada, Cystic Fibrosis Australia, and Novoteris. Dr. Flume also receives personal fees from Insmed outside this submitted work. Dr. VanDevanter reports personal fees from AbbVie, Albumedix, AN2, Aradigm, Armata, Arrevus, Calithera, Chiesi USA, Cipla, Corbus, Cystic Fibrosis Foundation, Eloxx, Enbiotix, Eveo, Galephar, Horizon, IBF, ICON clinical sciences, Ionis, Kala, Merck, Microbion, NDA, Protalix, PTC, Pulmocide, Recida, Savara, Vast, and Vertex outside of this work. Dr. Waters reports grants from Gilead and Astrazenca outside of this work. Dr. Elborn reports grants from Innovative Medicines Institute, Framework Seven, European Commission, Medical Research Council, and Bronch UK during the conduct of the study. Dr. Saiman reports grants from the CF Foundation, Merck, and AztraZeneca outside of this work. Dr. Bell reports grants and other support from Vertex, Galapagos and AbbVie outside of this work. Acknowledgements This work was funded by the European Cystic Fibrosis Society, Cystic Fibrosis Foundation, Cystic Fibrosis Trust, Cystic Fibrosis Canada, and Cystic Fibrosis Australia. We are grateful to Christine Dubois for managing the coordination of the Antimicrobial Resistance International Working Group in Cystic Fibrosis and Mary Philips, Metro North Hospital and Health Service for her illustration skills. References [1] Flume PA, Waters VJ, Bell SC, VanDevanter DR, Elborn JS. Antimicrobial resistance in cystic fibrosis: does it matter? J Cyst Fibros 2018;17:687–9. [2] Doring G, Flume P, Heijerman H, Elborn JS. Treatment of lung infection in patients with cystic fibrosis: current and future strategies. J Cyst Fibros 2012;11(6):461–79. [3] Paskovaty A, Pflomm JM, Myke N, Seo SK. A multidisciplinary approach to antimicrobial stewardship: evolution into the 21st century. Int J Antimicrob Agents 2005;25(1):1–10. [4] MacDougall C, Polk RE. Antimicrobial stewardship programs in health care systems. Clin Microbiol Rev 2005;18(4):638–56. [5] Paterson DL. The role of antimicrobial management programs in optimizing antibiotic prescribing within hospitals. Clin Infect Dis 2006;42(2):S90–5. [6] Delit TH, Owens RC, McGowan JE, et al. Infectious Diseases Society of American and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis 2007;44(2):159–77. [7] Principi N, Esposito S. Antimicrobial stewardship in paediatrics. BMC Infect Dis 2016;16:424. doi:10.1186/s12879-016- 1772- z. [8] Goff DA. Antimicrobial stewardship: bridging the gap between quality care and cost. Curr Opin Infect Dis 2011;24(S1):S11–20. [9] The United Nations. World leaders commit to act on antimicrobial resistance. Sustainable Development Goals; 2016. September 21st, https://www.un.org/sustainabledevelopment/blog/2016/09/ world- leaders- commit- to- act- on- antimicrobial- resistance/. [10] UK: Department of Health. The health and social care act 2008: code of practice for health and adult social care on the prevention and control of infections and related guidance. London; 2009. Department of Health Advisory Committee on Antimicrobial Resistance and Healthcare Associated Infection (ARHAI) ANTIMICROBIAL STEWARDSHIP: “START SMART - THEN FOCUS” Guidance for antimicrobial stewardship in hospitals (England). [11] Europe: European Council. Council Recommendation of 15.11.2001 on the Prudent Use of Antimicrobial Agents in Human Medicine (2002/77/EC). OJ L34 of 5.2.2002, p. 13. [12] Meeker D, Linder JA, Fox CR, Friedberg MW, Persell SD, Goldstein NJ, et al. Effect of behavioral interventions of inappropriate antibiotic prescribing

[13]

[14]

[15]

[16]

[17]

[18]

[19] [20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31] [32]

[33]

[34] [35]

[36]

[37]

[38]

9

among primary care practices: a randomized clinical trial. J Am Med Assoc 2016;315(6):562–70. Davey P, Marwick CA, Scott CL, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev 2017 2: CD003543. Rzewuska M, Charani E, Clarkson JE, et al. Prioritizing research areas for antibiotic stewardship programmes in hospital: a behavioural perspective consensus paper. Clin Microbiol Infect 2019;25:163–8. Tamma PD, Avdic E, Keenan JF, et al. What is the more effective antibiotic stewardship intervention: pre-prescription authorization or post-prescription review with feedback? Clin Infect Dis 2017;64:537–43. Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams-Warren J, Vasiljev M, Borowitz D, Bowman CM, Marshall BC, Marshall S, Smith AL. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. NEJM 1999;340:23–30. Ratjen F, Munck A, Kho P, Angvalosi G. Treatment of early pseudomonas aeruginosa infection in patients with cystic fibrosis: the ELITE trial. Thorax 2010;65:286–91. Taccetti G, Campana S, Festini F, Mascherini M, Doring G. Early eradication therapy against pseudomonas aeruginosa in cystic fibrosis patients. Eur Respirat J 2005:458–61. Johnson C, Butler SM, Konstan MW, Morgan W, Wohl ME. Factors influencing outcomes in cystic fibrosis: a center-based analysis. Chest 2003;123:20–7. Schechter MS, Regelmann WE, Sawicki GS, et al. Antibiotic treatment of signs and symptoms of pulmonary exacerbations: a comparison by care site. Pediatr Pulmonol 2015;50:431–40. Somayaji R, Parkins MD, Shah A, Martiniano SL, Tunney MM, Kahle JS, Waters VJ, Elborn JS, Bell SC, Flume PA, VanDevanter DR. Antimicrobial susceptibility testing (AST) and associated clinical outcomes in individuals with cystic fibrosis: a systematic review. J Cyst Fibros 2019;18(2):236–43 Mar. Smith DJ, Ramsay KA, Yerkovich ST, Reid DW, Wainwright CE, Grimwood K, Bell SC, Kidd TJ. Pseudomonas aeruginosa antibiotic resistance in australian cystic fibrosis centres. Respirology 2016;21(2):329–37. Rosenfeld M, Emerson J, Accurso F, Armstrong D, Castile R, Grimwood K, et al. Diagnostic accuracy of oropharyngeal cultures in infants and young children with cystic fibrosis. Pediatric Pulmonol 1999;28:321–8. Jung A, Kleinau I, Dchonian G, Bauernfeind A, Chen C, Griese M, et al. Sequential genotyping of pseudomonas aeruginosa from upper and lower airways of cystic fibrosis patient. Eur Respirat J 2002;20:1457–63. Kidd TJ, Ramsay KA, Vidmar S, Carlin JB, Bell SC, Wainwright CE, et al. Pseudomonas aeruginosa genotypes acquired by children with cystic fibrosis by age 5 years. J Cyst Fibros 2015;14:361–9. Ronchetti K, Tame JD, Paisey C, Thia LP, Doull I, Howe R, et al. The CF-sputum induction trial to assess lower airway bacterial sampling in young children with cystic fibrosis: a prospective internally controlled interventional trial. Lancet Respirat Med 2018;6(6):461–71. Breuer O, Caudri D, Ranganathan S, Stick SM, Schultz A. The clinical significance of oropharyngeal cultures in young children with cystic fibrosis. Eur Respirat J 2018;51(5):1–9. McNally P, O’Rourke J, Fantino E, Chacko A, Pabary R, Turnbull A, et al. Pooling of bronchoalveolar lavage in children with cystic fibrosis does not adversely affect the microbiological yield or sensitivity in detecting pulmonary inflammation. J Cyst Fibros 2018;17(3):391–9. Saiman L, Siegel Jand the Cystic Fibrosis Foundation Consensus Conference on Infection Control Participants. Infection control recommendations for patients with cystic fibrosis: microbiology, important pathogens, and infection control practice to prevent patient-to-patient transmission. Infect Control Hosp Epidemiol 2003;24(5):S6–S52. Saiman L, Siegel JD, LiPuma JJ, Brown RF, Bryson EA, Chambers MJ, et al. Infection control and control guideline for cystic fibrosis: 2013 Update. Infect Control Hosp Epidemiol 2014;35(S1):S1–S67. Zemanick ET, Bell SC. Prevention of chronic infection with pseudomonas aeruginosa infection in cystic fibrosis. Curr Opin Pulm Med 2019;25(6):636–45. Wainwright CE, Vidmar S, Armstrong DS, Byrnes CA, Carlin JB, Cheney J, Cooper PJ, Grimwood K, Moodie M, Robertson CF, Tiddens HA. Effect of bronchoalveolar lavage-directed therapy on pseudomonas aeruginosa infection and structural lung injury in children with cystic fibrosis: a randomized trial. JAMA 2011;306(2):163–71. Touw DJ, Vinks A, Mouton JW, Horrevorts AM. Pharmacokinetic optimisation of antibacterial treatment in patients with cystic fibrosis. Current practice and suggestions for future directions. Clin Phamarcokinet 1998;35(6):436–59. Lee CKK, Boyle MP, Diener-West M, Brass-Ernst L, Noschese M, Zeitlin PL. Levofloxacin pharmacokinetics in adult cystic fibrosis. Chest 2007;131(3):796–802. Smyth A, Tan KHV, Hyman-Taylor P, Mulheran M, Lewis S, Stableforth D, Know A. Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations in cystic fibrosis—the TOPIC study: a randomized controlled trial. Lancet 2005;365:573–8. Flume PA, Mogayzel PJ, Robinson KA, Goss GH, Rosenblatt RL, Kuhn RJ, et al. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respirat Crit Care Med 2009;180(89):802–8. Zobell JT, Waters CD, Young DC, Stockmann C, Ampofo K, Sherwin CMT, et al. Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: II. Cephalosporins and Penicillins. Pediatric Pulmonol 2013;48:107–22. Tracy MC, Moss RB. The myriad challenges of respiratory fungal infection in cystic fibrosis. Pediatric Pulmonol 2018;53:S75–85.

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[39] Kidd TJ, Canton R, Ekkelenkamp M, Johansen HK, Gilligan P, LiPuma JJ, Bell SC, Elborn JS, Flume PA, VanDevanter DR, Waters VJ. Antimicrobial resistance in cystic fibrosis international working group. Definining antimicrobial resistance in cystic fibrosis. J Cyst Fibros 2018;17(6):696–704. [40] Zemanick E, Burgel PR, Taccetti G, Holmes A, Ratjen F, Byrnes CA, Waters VJ, Bell SC, VanDevanter DR, Elborn JS, Flume PA. Antimicrobial susceptibility testing in cystic fibrosis: a delphi approach to defining best practices. J Cyst Fibros 2019 (ahead of print). [41] Mogayzel PJ, Naureckas ET, Robinson KA, Mueller G, Hadjiliadis D, Hoag JB, Lubsch L, Hazle L, Sabadosa K, Marshall B. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2013;187(7):680–9. [42] Hauser AR, Jain M, Bar-Meir M, McColley SA. Clinical significance of microbial infection and adaptation in cystic fibrosis. Clin Microbiol Rev 2011:29–70. [43] Livermore DM. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? Clin Infect Dis 2002;34:634–40. [44] Lister PD, Wolter DJ, Hanson ND. Antibacterial-resistant pseudomonas aeruginosa: clinical impact and complex regulation of chromosomally encoded resistance mechanisms. Clin Microbiol Rev 2009;22(4):582–610. [45] Hancock RWE, Speert DP. Antibiotic resistance in pseudomonas aeruginosa: mechanisms and impact on treatment. Drug Resist Updates 20 0 0;3(4):247–55. [46] Moskowitz SM, Brannon MK, Dasgupta N, Pier M, Sgambati N, Miller AK, Selgrade SE, Miller SI, Denton M, Conway SP, Johansen HK, Hoiby N. PmrB mutations promote polymyxin resistance of pseudomonas aeruginosa isolated from colistin-treated cystic fibrosis patients. Antimicrob Agents Chemotherp 2012;56(2):1019–30. [47] Mulcahy LR, Burns JL, Lory S, Lewis K. Emergence of Pseudomonas aeruginosa strains producing high levels of persister cells in patients with cystic fibrosis. J Bacteriol2010: 6191-6199. [48] Kahl B, Hermmann M, Everding AS, Koch HG, Becker K, Harms E, et al. Persistent infection with small colony variant strains of Staphyloccocus aureus in patients with cystic fibrosis. J Infect Dis 1998;177:1023–9. [49] Wolter DJ, Emerson JC, McNamara S, Buccat AM, Qin X, Cochrane E, et al. Staphylococcus aureus small-colony variants are independently associated with worse lung disease in children with cystic fibrosis. Clin Infect Dis 2013;57(3):384–91. [50] Norstrom T, Lannergard J, Hughes D. Genetic and phenotypic identification of fusidic acid-resistant mutants with the small-colony-variant phenotype in Staphylococcus aureus. Antimicrob Agents Chemother 2007;51:4438–46. [51] Besier S, Smaczny C, von Mallinckrodt C, Krahl A, Ackermann H, Brade V, et al. Prevalence and clinical significance of Staphyloccocus aureus small-colony variants in cystic fibrosis lung disease. J Clin Microbiol 2007;45(1):168–72. [52] Junge S, Goerlich D, den Reijers M, Wiedemann B, Tummler B, Ellemunter H, Dubbers A, Kuster P, Ballmann M, Koerner-Rettber C, Grobe-Onnebrink J, Heuer E, Sextro W, Mainz JG, Hammermann J, Riethmuller J, Graepler– Mainka Y, Staab D, Wollschlager B, Szczepanski R, Schuster A, Tegtmeyer FK, Suthersan S, Wald A, Nofer JR, van Wamel W, Becker K, Peters G, Kahl BC. Factors associated with worse lung function in cystic fibrosis patients with persistent Staphylococcus aureus. PLoS ONE 2016;11(11):e0166220. [53] Smyth AR, Rosenfeld M. Prophylactic anti-staphylococcal antibiotics for cystic fibrosis. Cochrane Database Syst Rev 2017;4 Apr 18;CD001912. [54] CF START: A National UK Trial to Determine Whether Taking an Antibiotic (flucloxacillin) Every Day Predisposes Infants with Cystic Fibrosis (CF) to Earlier Infection with a Bug, Pseudomonas aeruginosa, that is Resistant to Treatment. ISRCTN Registry http://www.cfstart.org.uk. [55] Burns JL, Emerson J, Stapp JR, Yim DL, Krzewinski J, Louden L, Ramsey BW, Clausen CR. Microbiology of sputum from patients at cystic fibrosis centers in the United States. Clin Infect Dis 1998;27(1):158–63. [56] Burns JL, Van Dalfsen JM, Shawar RM, Otto KL, Garber RL, Quan JM, Montgomery AB, Albers GM, Ramsey BW, Smith AL. Effect of chronic intermittent administration of inhaled tobramycin on respiratory microbial flora in patients with cystic fibrosis. J Infect Dis 1999;179(5):1190–6. [57] Harun SN, Holford NHG, Grimwood K, Wainwright CE, Hennig S. Pseudomonas aeruginosa eradication therapy and risk of acquiring aspergillus in young children with cystic fibrosis. Thorax 2019;74(8):740–8. [58] Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and management of penicillin allergy: a review. J Am Med Assoc 2019;321(2):188–99 15. [59] Prayle A, Watson A, Fortnum H, Smyth A. Side effects of aminoglycosides on the kidney, ear and balance in cystic fibrosis. Thorax 2010;65:654–8. [60] Massie J, et al. Pharmacokinetic profile of once daily intravenous tobramycin in children with cystic fibrosis. J Paediatric Child Health 2006;42(10):601–5. [61] Goss C. Standardized Treatment of Pulmonary Exacerbations II (STOP 2). ClinicalTrials. gov NCT02781610. [62] Cogen JD, Hall M, Loeffler DR, Gove N, Onchiri F, Sawicki GS, et al. Linkage of the cystic fibrosis foundation patient registry with the pediatric health information system database. Pediatr Pulmonol 2019. doi:10.1002/ppul.24272. [63] CF Learning Network. Available from https://www.cflearningnetwork.org/whatwe-do/; Accessed date: April 26th, 2019. [64] Morris AM, Bai A, Burry L, et al. Long-term effects of phased implementation of antimicrobial stewardship in academic ICUs: 2007-2015. Crit Care Med 2019;47:159–66. [65] So M, Mamdani MM, Morris AM, et al. Effect of an antimicrobial stewardship programme on antimicrobial utilisation and costs in patients with leukaemia: a retrospective controlled study. Clin Microbiol Infect 2018;24:882–8.

[66] So M, Yang DY, Bell C, Humar A, Morris A, Husain S. Solid organ transplant patients: are there opportunities for antimicrobial stewardship? Clin Transplant 2016;30:659–68. [67] Rowbotham NJ, Smith S, Leighton PA. The top 10 research priorities in cystic fibrosis developed by a partnership between people with CF and healthcare providers. Thorax 2018;73(4):388–90. [68] Dijkema JS, van Eqijk BE, Wilbrink B, Wolfs TF, Kimpen JL, van der Ent CK. Frequency and duration of rhinovirus infections in children with cystic fibrosis and healthy controls: a longitudinal cohort study. Pediatr Infect Dis J 2016;35:379–83. [69] Cousin M, Molinari N, Foulongne V, Caimmi D, Vachier I, Abely M, Chiron R. Rhinovirus-associated pulmonary exacerbations show a lack of FEV1 improvement in children with cystic fibrosis. Influenza Other Respir Viruses 2016;10(2):109–12. [70] Hendricks MR, Lashua LP, Fischer DK, Flitter BA, Eichinger KM, Durbin JE, Sarkar SN, Coyne CB, Empey KM, Bomberger JM. Respiratory syncytial virus infection enhances Pseudomonas aeruginosa biofilm growth through dysregulation of nutritional immunity. PNAS 2016;113(6):1642–7. [71] Chattoraj SS, Ganesan S, Jones AM, Helm JM, Comstock AT, Bright-Thomas R, LiPuma JJ, Hershenson MB, Sajjan US. Rhinovirus infection liberates planktonic bacteria from biofilm and increases chemokine responses in cystic fibrosis airway epithelial cells. Thorax 2011;66(4):333–9. doi:10.1136/thx.2010.151431. [72] Chin M, De Zoysa M, Slinger R, et al. Acute effects of viral respiratory infections on bacterial sputum density during CF pulmonary exacerbations. J Cyst Fibros 2015;14:482–9. [73] Asner S, Waters V, Solomon M, et al. Role of respiratory viruses in pulmonary exacerbations in children with cystic fibrosis. J Cyst Fibros 2012;11:433–9. [74] Castanheira M, Deshpande LM, Costello A, Davies TA, Jones RN. Epidemiology and carbapenem resistance mechanisms of carbapenem-non-susceptible pseudomonas aeruginosa collected during 2009-2011 in 14 European and mediterranean countries. J Antimicrob Chemother 2014;69(7):1804–14. [75] Tai AS, Kidd TJ, Whiley DM, Ramsay KA, Buckley C, Bell SC. Molecular surveillance for carbapenemase genes in carbapenem resistant pseudomonas aeruginosa in australian patients with cystic fibrosis. Pathology 2015;47(2):156–60. [76] Einarsson GG, Flanagan E, Lee AJ, McGettigan C, Smith C, Gilpin DE, et al. Microbiota profiling during 1-year of clinical stability in people with cystic fibrosis-CFMATTERS consortium. Abstract. J Cyst Fibros 2019:18S1:S35. [77] Foweraker JE, Laughton CR, Brown DF, Bilton D. Comparison of methods to test antibiotic combinations against heterogenous populations of multiresistant pseudomonas aeruginosa from patients with acute infective exacerbations in cystic fibrosis. Antimicrob Agents Chemother 2009;53(11):4809–15. [78] Foweraker JE, Laughton CR, Brown DF, Bilton D. Phenotypic variability of pseudomonas aeruginosa in sputa from patients with acute infective exacerbation of cystic fibrosis and its impact on the validity of antimicrobial susceptibility testing. J Antimicrob Chemother 2005;55(6):921–7. [79] Dallal RM, Harbrecht BG, Boujoukas AJ, et al. Fulminant clostridium difficile: an underappreciated and increasing cause of death and complications. Ann Surg 2002;235:363–72. [80] Peach SL, Borriello SP, Gaya H, Barclay FE, Welch AR. Asymptomatic carriage of clostridium difficile in patients with cystic fibrosis. J Clin Pathol 1986;39:1013–18. [81] Egressy K, Jansen M, Meyer KC. Recurrent clostridium difficile colitis in cystic fibrosis: an emerging problem. J Cyst Fibros 2013;12:92–6. [82] Rivlin J, Lerner A, Augarten A, Wilschanski M, Kerem E, Ephros MA. Severe clostridium difficile-associated colitis in young patients with cystic fibrosis. J Pediatr 1998;132(1):177–9. [83] Yates B, Murphy DM, Fisher AJ, Gould FK, Lordan JL, Dark JH, Corris PA. Pseudomembranous colitis in four patients with cystic fibrosis following lung transplantation. Thorax 2007;62:554–6. [84] Patriarchi F, Rolla M, Maccioni F, Menichella A, Scacchi C, Ambrosini A, et al. Clostridium difficile-related Pancolitis in lung-transplanted patients with cystic fibrosis. Clin Transplant 2011;25(1):E46–51. [85] McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for clostridium difficile infection in adults and children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 2018;66(4):e1–e48. [86] Al-Aloul M, Miller H, Alapati S, Stockton PA, Ledson MJ, Walshaw MJ. Renal impairment in cystic fibrosis patients due to repeated intravenous aminoglycoside use. Pediatr Pulmonol 2005;39:15–20. [87] Garinis AC, Cross CP, Srikanth P, Carroll K, Feeney MP, Keefe DH, et al. The cumulative effects of intravenous antibiotic treatments on hearing in patients with cystic fibrosis. J Cyst Fibros 2017;16:401–9. [88] Al-Malky G, Dawson SJ, Sirimanna T, Bagkeris E, Suri R. High-frequency audiometry reveals high prevalence of aminoglycoside ototoxicity in children with cystic fibrosis. J Cyst Fibros 2015;14:248–54. [89] Al-Malky G, Dawson SJ, Sirimanna T, Bagkeris E, Suri R. High-frequency audiometry reveals high prevalence of aminoglycoside ototoxicity in children with cystic fibrosis. J Cyst Fibros 2015;14:248–54. [90] De Geller, WH Pitlick, Nardella PA, Tracewell WG, Ramsey BW. Pharmacokinetics and bioavailability of aerosolized tobramycin in cysitc fibrosis. Chest 2002;122:219–26. [91] Smith S, Rowbotham NJ, CHarbek E. Inhaled antibiotics for pulmonary exacerbations in cystic fibrosis. Cochrane Database Syst Rev 2018:10 NO.:CD008319. doi:10.10 02/14651858.CD0 08319.pub3.

Please cite this article as: J.D. Cogen, B.C. Kahl and H. Maples et al., Finding the relevance of antimicrobial stewardship for cystic fibrosis, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2020.02.012