5.527 Journal of Cystic Fibrosis The Official Journal of the European Cystic Fibrosis Society www.ECFS.eu Volume 21 Issue 4 July 2022 ISSN 1569-1993 In this Issue: Modeling pulmonary cystic fibrosis in a human lung airway-on-a-chip October 2022 Volume 21, S2 Abstracts of the North American Cystic Fibrosis Conference November 3–5, 2022 October 2023 Volume 22, S3 November 2–4, Phoenix, Arizona 5.2 2023 North American Cystic Fibrosis Conference
Editorial Board Editor-in-Chief: Patrick Flume, Medical University of South Carolina, Charleston, South Carolina, USA Deputy Editors: Carlo Castellani, IRCCS Instituto Giannina Gaslini, Cystic Fibrosis Centre, Genoa, Italy Jane Davies, National Heart & Lung Institute, Imperial College London and Royal Brompton and Harefield NHS Foundation Trust, London, UK Editorial Board: Scott Blackman, USA Pierre-Régis Burgel, France Scott Donaldson, USA Aleksander Edelman, France Pascale Fanen, France Carlos Farinha, Portugal Hubert E. Hatcher, USA Sonya Heltshe, USA Niels Høiby, Denmark Dominic Hughes, UK Andrea Kelly, USA Susannah King, Australia Paul McCray, USA Marianne Muhlebach, USA KeithOoi, Australia Nicoletta Pedemonte, Italy Gerald Pier, USA Felix Ratjen, Canada Kristin A. Riekert, USA Dorota Sands, Poland Rhonda Szczesniak, USA Anne Stephenson, Canada Cliff Taggart, UK Jennifer Taylor-Cousar, USA DaanTouw, The Netherlands Michael Tunney, N. Ireland Donald Van Devanter, USA Valerie Waters, Canada Michael Wilschanski, Israel Jeffrey Wine, USA Editor In Chief, Cystic Fibrosis Research News: Harry Heijerman, University Medical Center Utrecht, The Netherlands Previous Editors-in-Chief: Harry Heijerman, University Medical Center Utrecht, The Netherlands Gerd Döring, University of Tübingen, Tübingen, Germany Scott Bell, The Prince Charles Hospital, Queensland, Australia Amsterdam — Boston — London — New York — Oxford — Paris — Philadelphia — San Diego — St. Louis — Tokyo
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Volume 21 (2022) Publication of this Abstract Supplement is supported by The Cystic Fibrosis Foundation. Abstracts of the North American Cystic Fibrosis Conference November 3–5, 2022 Volume 21, Supplement 2 (2022) 2023 North American Cystic Fibrosis Conference November 2–4, 2023 Phoenix, Arizona Volume 22, Supplement 3 (2023)
Contents, Volume 17 (2018) Supplement Abstracts of the 40th European Cystic Fibrosis Conference Seville, Spain, 7–10 June 2017 Workshops S1 Workshop 1. Old and new thoughts on antibiotics ............................................................................ S1 Workshop 2. Nutrition: from daily practice to enzymes for the future ............................................ S3 Workshop 3. New therapies targeting the airway surface ................................................................. S4 Workshop 4. New insights from inflammation and immunology...................................................... S6 Workshop 5. Anxiety and depression: a family affair ........................................................................ S7 Workshop 6. CFTR dysfunction: what happens where? ..................................................................... S9 Workshop 7. Microbiome analysis in CF: what’s new in lung and gut?............................................ S11 Workshop 8. CT and MRI, where are we? Ready yet for the clinics? ................................................ S12 Workshop 9. Exercise and correlations with other outcomes............................................................ S14 Workshop 10. The impact of CF: high mountains – deep valleys ...................................................... S16 Workshop 11. Newborn screening and diagnostic advances .............................................................. S17 Workshop 12. Bone health, glucose metabolism and CFRD ............................................................... S19 Workshop 13. Rescuing CFTR: new developments ............................................................................. S20 Workshop 14. Basic pathogenesis: Pseudomonas, microbiota interaction and viruses...................... S22 Workshop 15. New lung function methods to monitor disease and treatment ................................ S24 Workshop 16. Understanding and teaching, a knowledge network................................................... S26 Workshop 17. CF related liver disease and pancreatic insufficiency: can we do better? .................. S28 Workshop 18. CFTR: Functional tests for therapeutic interventions.................................................. S29 Workshop 20. Evolving epidemiology and risk factors for lung infection......................................... S31 Workshop 21. How to personalise chest physiotherapy? ................................................................... S32 Workshop 23. Insights from registries and cohorts............................................................................ S34 ePS01. Screening and Diagnosis ........................................................................................................... S36 ePS02. The CF team in development ................................................................................................... S39 ePS03. New treatments ........................................................................................................................ S41 ePS04. Multi-tasking physiotherapists: managing hygiene, pain, exercise, . . . .................................. S43 2 21 2022 Abstracts of the North American Cystic Fibrosis Conference November 3–5, 2022 Poster Categories �����������������������������������������������������������������������������������������������������������������������������������������������������������S1 Endocrine/Bone �����������������������������������������������������������������������������������������������������������������������������������������������������������������������������S1 Epidemiology & Population-based Research����������������������������������������������������������������������������������������������������������������������S12 Quality Improvement���������������������������������������������������������������������������������������������������������������������������������������������������������������� S35 Pulmonary ������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������ S66 Transplantation ��������������������������������������������������������������������������������������������������������������������������������������������������������������������������� S84 Clinical Genetics ������������������������������������������������������������������������������������������������������������������������������������������������������������������������� S87 Clinical Trials & Outcome Measures������������������������������������������������������������������������������������������������������������������������������������� S89 GI/Nutrition ��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������� S110 Nursing Issues ��������������������������������������������������������������������������������������������������������������������������������������������������������������������������� S142 Pharmacy ������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������ S146 Physical & Respiratory Therapy ������������������������������������������������������������������������������������������������������������������������������������������� S157 Psychosocial/Behavioral ��������������������������������������������������������������������������������������������������������������������������������������������������������� S166 Education ������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������ S199 Health Equity, Care, Delivery & Access to Care ���������������������������������������������������������������������������������������������������������������S207 Airways Physiology, Pathophysiology & Airways Defense ������������������������������������������������������������������������������������������ S223 Infection/Microbiology ����������������������������������������������������������������������������������������������������������������������������������������������������������� S260 Extrapulmonary Physiology & Pathophysiology �������������������������������������������������������������������������������������������������������������S317 Path to a Cure ����������������������������������������������������������������������������������������������������������������������������������������������������������������������������S327 CFTR ���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������� S352 This abstract book has been produced electronically by Elsevier B�V�, and is also available on USB� Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein� Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made� To the fullest extent of the law, no responsibility is assumed by Elsevier or the European Cystic Fibrosis Society for any injury and/ or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein� 3 22 2023 2023 North American Cystic Fibrosis Conference November 2–4, 2023 Infection/Microbiology ���������������������������������������������������������������������������������������������������������������������������������������������������������������� S1 Clinical Trials & Outcome Measures ....................................................................................................................................S55 Airways Physiology, Pathophysiology & Airways Defense.............................................................................................S78 Path to a Cure..............................................................................................................................................................................S118 CFTR.............................................................................................................................................................................................. S143 Clinical Genetics........................................................................................................................................................................S167 Extrapulmonary Physiology & Pathophysiology.............................................................................................................S175 Education. ................................................................................................................................................................................... S185 Health Equity, Care, Delivery, & Access to Care...............................................................................................................S189 Nursing Issues.............................................................................................................................................................................S211 Pharmacy..................................................................................................................................................................................... S218 Physical & Respiratory Therapy............................................................................................................................................S234 Psychosocial/Behavioral......................................................................................................................................................... S242 GI/Nutrition................................................................................................................................................................................ S270 Endocrine/Bone......................................................................................................................................................................... S297 Epidemiology & Population-Based Research...................................................................................................................S310 Quality Improvement..............................................................................................................................................................S339 Pulmonary................................................................................................................................................................................... S390 Transplantation.........................................................................................................................................................................S406 This abstract book has been produced electronically by Elsevier B.V., and is also available on USB. experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier or the European Cystic Fibrosis Society for any injury and/ instructions, or ideas contained in the material herein.
INFECTION/MICROBIOLOGY 1 High Ca++ does not hinder cyclic diguanosine monophosphate– mediated control of the Pseudomonas aeruginosabiofilm life cycle M. Graz1, J. Andersen1, L. Hultqvist1, C. Jansen2, T. Holm Jakobsen1, M. Nilsson1,M. Rybtke1, B. Fritz1, R. Seifert3, T. Nielsen1, K. Qvortrup2, T. Tolker-Nielsen1, M. Givskov1. 1Costerton Biofilm Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 2Department of Chemistry, Technical University of Denmark, Lyngby, Denmark; 3Institute of Pharmacology and Research Core Unit Metabolomics, Hannover Medical School, Hannover, Germany Background: Recent evidence suggests that mucoid Pseudomonas aeruginosapossesses a Ca++-dependent mechanism for biofilm formation [1] not dependent on cyclic diguanosine monophosphate (c-di-GMP), which is generally considered necessary for biofilm formation in G– bacteria [2]. Furthermore, the calcium chloride (CaCl2)-rich lung environment of the CF lung is claimed to prevent c-di-GMP control of biofilms [1]. The c-di-GMP– degrading protein BifA is an anti-biofilm biofilm drug target [3]. We developed Disperazol (Figure 1A) to directly activate BifA, which exhausts the P. aeruginosa c-di-GMP pool, drives biofilm bacteria to become planktonic, and allows for efficient killing of the dispersed bacteria with standard-of-care antibiotics. We have challenged the assumption that c-diGMP–controlled biofilm dissolution is inhibited by CaCl2 and show that exopolysaccharide over-producing variants of P. aeruginosa respond to modulation of c-di-GMP levels even in the presence of high levels of CaCl2. Methods: The efficacy of Disperazol (Figure 1A) was examined using a standard crystal violet assay [3]. The parent P. aeruginosa PAO1 wild type and the mucoidmucA22alginate overproducer were compared (Figure 1B). Biofilms were exposed to Disperazol for 1 hour before staining. The efficiency of Disperazol-tobramycin treatment (expressed as reduction in CFUs) was assessed in a setup comprising polystyrene pegs protruding perpendicularly from the plastic lids into the wells of a microtiter plate [3]. PAO1 wild type, mucA22, and wspF (Psl and Pel overproducer) were compared (Figure 1C). Results: We demonstrate that biofilms of P. aeruginosa mucA22 are sensitive to modulation of c-di-GMP levels in the presence of CaCl2 (Figure 1B). Transient exposure to Disperazol dismantles biofilms of the mucA22alginate over-producing strain as thewt parent. We also show that activation of BifA by Disperazol demonstrates a synergistic antimicrobial effect leading to more than a 100-fold increase in efficacy of standard-ofcare antibiotics on the biofilm life-mode (Figure 1C). We verified this by showing that Disperazol induces dispersal and prevents biofilm formation in several mucoid clinical isolates obtained from people with CF. Figure 1. (A) Disperazol (HCl salt), (B) Biofilm dispersal with disperazol, (C) Highefficacy biofilm eradication with tobramycin and disperazol Conclusions: Our evidence indicates that c-di-GMP concentration– mediated control of mucoid P. aeruginosa biofilm includes conditions of highCa++ concentrations. It strongly suggests that c-di-GMP concentration is a central regulatory determinant of mucoid and other exopolysaccharide over-producing P. aeruginosa biofilms. Disperazol co-therapy with standard-of-care antibiotics may therefore remain as a future target. Disperazol is being evaluated not only in clinical isolates from persons with CF, but also for other indications in whichP. aeruginosais the prime pathogen, such as non-CF bronchiectasis, ventilator-associated pneumonia, catheter-associated urinary tract infections [4] and ulcerating wounds. References [1] Jacobs HM, O’Neal L, Lopatto E, Wozniak DJ, Bjarnsholt T, Parsek MR. Mucoid Pseudomonas aeruginosa can produce calcium-gelled biofilms independent of the matrix components Psl and CdrA. J Bact 2022;204 (5). https://doi.org/10.1128/jb.00568-21 Journal of Cystic Fibrosis 22S3 (2023) S1–S408
[2] Jenal U, Reinders A, Lori C. Cyclic di-GMP: second messenger extraordinaire. Nat Rev Microbiol 2017;15:271–284. https://doi.org/10. 1038/nrmicro.2016.190 [3] Andersen JB, Dahl Hultqvist L, Uldahl Jansen C, Holm Jakobsen T, Nilsson M, Rybtke M, et al. Identification of small molecules that interfere with c-di-GMP signaling and induce dispersal of Pseudomonas aeruginosa biofilms. NPJ Biofilms Microbiomes 2021;7:59. https://doi.org/10.1038/s41522-021-00225-4 [4] Hultqvist L, Andersen JB, Jansen C, Graz M, Tolker-Nielsen T, Givskov M. High efficacy treatment of Pseudomonas aeruginosa catheterassociated urinary tract infections using Disperazol in combination with ciprofloxacin. Forthcoming. 2 Targeting cystic fibrosis Pseudomonas aeruginosa with galactoserelated glycomimics: α- and β-anomeric configurations, Nacetylation, and sulfation in whole-cell binding D. Chance1,2,W.Wang3,4, T. Mawhinney2,3. 1Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO; 2Department of Child Health, University of Missouri, Columbia, MO; 3Department of Biochemistry, University of Missouri, Columbia, MO; 4Microbiomics Lab, Fudan University, Shanghai, China Background: Pseudomonas aeruginosa is a key player in the frequent and eventually chronic respiratory infections of persons with CF. Despite progress with CF modulator therapies, bacterial multidrug resistance prevails, andP. aeruginosaremains difficult to eradicate. Novel CF infection treatment approaches are needed to complement the current arsenal of inhaled antibiotics. One strategy in development involves targeting of antimicrobial agents to the bacterial biofilm through the carbohydrate binding adhesins [1–3]. Our ongoing surveys of CF P. aeruginosa monosaccharide binding profiles suggest that tags with certain galactose-related entities may prove useful at directly targeting theP. aeruginosa outer membrane. Methods: Using water soluble polyacrylamide-based fluorescent glycopolymers (PAA-Fluors) withα-orβ-configurations locked in place for pendant side chain monosaccharides related to galactose (Gal), CF P. aeruginosa isolates (n = 8) from sputum and throat cultures and one control P. aeruginosa (ATCC BAA47) were screened for preferred solution-phase monosaccharide binding. Bacterial suspensions were exposed to α-Gal, βGal, α-N-acetyl-galactosamine (α-GalNAc), β-GalNAc, or the sulfate (S) ester-possessing β-Gal3S or β-GalNAc3S PAA-Fluors. The bacterial-glycopolymer reactions were rinsed of free glycopolymer and then examined using fluorescence microscopy in microwell microscope slides and spectrofluorometrically in 96-well plates. Results: Positive P. aeruginosa-glycopolymer binding reactions visually yielded fluorescent cells in a field of nonfluorescent cells, and spectrofluorometrically quantifiable positive fluorescence intensities (FI) unlike the negative control reactions with aminoglucitol-PAA-FLUOR. α-Gal, βGalNAc, andβ-Gal3S glycopolymers showed distinctly positive binding for each CF isolate and the laboratoryP. aeruginosastandard. The FI values of P. aeruginosa strains per glycopolymer ranged as follows: α-Gal 12K-34 K; βGal 2K-4.8 K; α-GalNAc 1.6K-4.7 K; β-GalNAc 8K-22 K; β-Gal3S 10K-32 K; βGalNAc3S 1K-5 K; and aminoglucitol-PAA-FLUOR 500-2.4 K. Transmission electron microscopy imaging of representative α-Gal and β-Gal binding reactions after immunogold labeling through the fluorescein entity confirmed that the binding was specifically at the cell surface for α-Gal and was not even diffusely present for the β-Gal glycopolymer. Conclusions: α-Gal not β-Gal, β-GalNAc not α-GalNAc, and β-Gal3S not βGalNAc3S, were the specific preferred galactose-type monosaccharides for the CF P. aeruginosa surveyed. Based on these glycopolymer binding data, we suggest using the specific configurations of α-Gal or β-GalNAc in glycomimetics designed to target antibiotics, drug-resistance pump inhibitors, or other agents to CF host-adaptedP. aeruginosa cells. Acknowledgements: This work was supported by the Cystic Fibrosis Associations of Missouri and West Plains, the Leda J. Sears Trust, and the University of Missouri Experiment Station Chemical Laboratories. References [1] Meiers J, Zahorska E, Röhrig T, Hauck D, Wagner S, Titz A. Directing drugs to bugs: antibiotic-carbohydrate conjugates targeting biofilmassociated lectins of Pseudomonas aeruginosa. J Med Chem 2020;63 (20):11707–24. https://doi.org/10.1021/acs.jmedchem.0c00856. [2] Limqueco E, Passos Da Silva D, Reichhardt C, Su F-Y, Das D, Chen J, etal. Mannose conjugated polymer targetingP. aeruginosabiofilms. ACS Infect Dis 2020;6(11):2866–71. https://doi.org/10.1021/acsinfecdis. 0c00407. [3] Boffoli D, Bellato F, Avancini G, Gurnani P, Yilmaz G, Romero M, Robertson S, et al. Tobramycin-loaded complexes to prevent and disrupt Pseudomonas aeruginosa biofilms. Drug Deliv Transl Res 2021. https://doi.org/10.1007/s13346–021-01085-3. 3 ELD607, a novel Orai1 antagonist, reduces inflammation and clears Burkholderia cepacia complex and multidrug-resistant Pseudomonas aeruginosafrom the lungs S. Ahmad1, F. Sassano2, R. Tarran3. 1Eldec Pharmaceuticals, Durham, NC; 2Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC; 3University of North Carolina at Chapel Hill, Chapel Hill, NC Background: The Burkholderia cepacia complex (Bcc) is a group of 20 genetically distinct species. Although generally harmless to humans, they are extremely pathogenic to persons with CF, and acquisition of Bcc is associated with a significant increase in mortality. Treatment of Bcc infections are difficult because the bacteria are multidrug resistant. There has been a rise in infection with multidrug-resistant Pseudomonas aeruginosa (MDR-Pa) that is poorly responsive to treatment, resulting in increased CF exacerbations and hospitalization. Therefore, there is an unmet need for novel Bcc and MDR-Pa treatments. Orai1 is a plasma membrane Ca2+ channel that regulates the immune system. We hypothesized that local Orai1 inhibition in the lungs would reduce inflammation and help clear bacterial infection. We tested whether inhaled ELD607 could reduce pulmonary Bcc and MDR-Pa infections in mice. Methods: To determine if ELD607 reduced inflammation and infection, an in vivo infection murine model was used. Mice were infected with 107CFU/ mouse Bcc strainB. cenocepacia J2315 or a clinical isolate of MDR-Pa (Paer 16) and then treated with 0.5 mg/kg ELD607 or saline (controls) intranasally. To determine if macrophages underpinned the ELD607induced increase in bacterial clearance and phagocytosis, mice were treated intratracheally with liposomes containing clodronate to deplete alveolar macrophages. 48 hours after clodronate administration, mice were infected with P. aeruginosa PAO1 and treated with ELD607 or saline. Bronchoalveolar lavage and lungs were collected 24 hours after infection to determine inflammatory cell expression, lung damage, and bacterial burden. Results: Mice infected with Bcc or MDR-Pa had an increase in neutrophils, although there was significant normalization of lung leukocyte levels when treated with ELD607. Bacterial burden in the lungs was significantly reduced by approximately 2 log10 in mice treated with ELD607. Overall weight of mice treated with ELD607 was normalized (n = 5 mice/group, p < 0.01). Additionally, in mice pretreated with clodronate to deplete macrophages, ELD607 did not reduce neutrophils or reduce bacterial burden in the lungs (n = 8 mice/group). Conclusions: ELD607 lowered neutrophilia and promoted macrophagemediated resolution of inflammation regardless of pathogen. ELD607 reduced lung bacterial burden of Bcc and MDR-Pa. ELD607 may be a novel therapeutic to clear antibiotic-resistant bacteria from CF lungs. Acknowledgements: Funded by the CFF, NIH/NIAID and NIH/NHLBI. Journal of Cystic Fibrosis 22S3 (2023) S1–S408 S2
4 Diagnostic utility of plasma microbial cell-free DNA sequencing in people with cystic fibrosis M. Wasserman1,2,3, J. Greenberg4, B. Hall4, G. Sawicki3,4, G. Priebe3,5,6. 1Division of Hospital Medicine, Boston Children’s Hospital, Boston, MA; 2Department of Pediatrics, Boston Children’s Hospital, Boston, MA; 3Harvard Medical School, Boston, MA; 4Division of Pulmonary Medicine, Boston Children’s Hospital, Boston, MA; 5Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, MA; 6Division of Infectious Diseases, Department of Pediatrics, Boston Children’s Hospital, Boston,MA Background: Despite overall improvements in the health of people with CF, acute pulmonary exacerbations (APEs) remain a common occurrence and are associated with numerous adverse health outcomes. Current clinical methods to characterize CF lung infection and determine appropriate antibiotic regimens rely on sputum or throat cultures, which are limited by time, media, growth, and sampling technique. Plasma microbial cell-free DNA sequencing (Karius Testing) has recently become available in the clinical setting to assist in the non-culture-based diagnosis of infectious diseases, including community- and hospital-acquired pneumonia without bacteremia, indicating that organ-space infection can be diagnosed from microbial cell-free DNA fragments in the blood. We hypothesized that Karius Testing would detect CF-relevant microbes, particularly in those with advanced lung disease. Methods: Karius Testing (expressed as DNA molecules per microliter [MPM]) was performed on biobanked plasma samples collected from 27 people with CF, 21 (78%) at their baseline health and 6 (22%) during APEs, and compared with respiratory culture results taken within 2 weeks of plasma collection. Results: Participants had a median age of 24 (IQR 13) (range 5–52) and mean ± SD ppFEV1 of 73 ± 28%; 59% were taking CFTR modulators. In the exacerbation cohort, 67% (4/6) of the samples identified a microbe on Karius Testing that was concordant with respiratory culture results, compared with 48% (10/21) of the samples taken from participants at their clinical baseline. All 9 participants with respiratory cultures that grew Pseudomonas aeruginosa showed P. aeruginosa on Karius Testing. Karius Testing identifiedStaphylococcus aureus in only one of the plasma samples, obtained in a subject at baseline health, despite S. aureus growth in respiratory cultures from 17 participants. Of the 13 samples from individuals with ppFEV1 less than 70%, 77% (10/13) showed concordance of respiratory cultures with Karius Testing for a CF-relevant microbe, compared with 29% (4/14) of those with ppFEV1≥70% (P = 0.021 by Fisher exact test). Karius Testing identified Burkholderia cepacia complex in a 5year-old participant and Bacteroides fragilis in a 20-year-old participant, both at low MPM, despite no growth of these organisms on recent respiratory cultures. Conclusions: Our results suggest that plasma microbial cell-free DNA sequencing using the Karius platform in people with CF holds promise in detecting CF-relevant microbes, particularly P. aeruginosa. Karius testing was negative in nearly all patients growingS. aureus in respiratory cultures, raising questions about the pathogenicity of S. aureus in CF. Karius Testing can identify CF-relevant microbes not detected in accompanying respiratory cultures. Prospective studies are needed to assess the potential utility of the Karius test in the clinical management of people with CF. Acknowledgements: This work was supported in part by the Institutional Centers for Clinical and Translational Research at Boston Children’s Hospital. We thank Karius (Redwood City, CA) for covering the costs of Karius Testing. 5 Nontuberculous mycobacterial infection as a barrier to lung transplantation in people with cystic fibrosis C.Mingora1, A. Boan2,3,4, P. Flume2,5. 1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, Medical University of South Carolina, Charleston, SC; 2Department of Pediatrics, Medical University of South Carolina, Charleston, SC; 3Department of Neurology, Medical University of South Carolina, Charleston, SC; 4Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC; 5Department of Medicine, Medical University of South Carolina, Charleston, SC Background: Nontuberculous mycobacteria (NTM) are pathogens of significance that may be isolated from the airways of people with CF (PwCF). Organisms fromMycobacterium aviumcomplex and M. abscessus complex (Mabsc) are the most frequently isolated. These organisms may be transiently or persistently present in the airways and are known to be associated with adverse outcomes, including reduced lung function and accelerated rate of lung function decline. In addition to complicating general CF management, infection with NTM may also play a part in decisions regarding lung transplantation, with wide variation in clinical practice and identification of NTM as respiratory pathogens that may increase risk of post-transplantation complications. This study seeks to better understand real-world practices in lung transplant referral, evaluation, and performance in PwCF with NTM present in respiratory cultures. Methods: The Cystic Fibrosis Foundation Patient Registry (CFFPR) was queried from 2010 to 2019 to identify patients aged 18 and older with available mycobacterial culture data. Those with cultures positive for M. tuberculosis and those with history of prior lung transplantation were excluded. Primary analysis included patients with average ppFEV1of30%or less. A second analysis included those with ppFEV1 of 40% or less with additional markers of disease severity as outlined in the CFF lung transplant referral guidelines using surrogate measures as available in the CFFPR (use of continuous supplemental oxygen therapy, history of massive hemoptysis, history of pneumothorax requiring chest tube placement). Key patient demographic characteristics, genotype, modulator status, complete microbiologic assessment, lung transplant status as defined in the CFFPR questionnaire, and defined markers of disease severity were identified. Participants were compared according to NTM status. Descriptive statistics and measures of association were determined. Results: A total of 20,014 unique individuals were identified; 3,358 had ppFEV1 of 30% or less and 3,816 had ppFEV1 of 40% or less with at least one marker of disease severity. Of those with ppFEV1 of 30% or less, 1,926 were male (57.3%), 1,250 (38%) had a single copy of F508del mutation, 1,673 (51.2%) were homozygous for F508del mutation, and 1,345 (40.0%) were prescribed CFTR modulator therapy. NTM was identified at least once in respiratory culture in 805 (24%) people. Odds ratios for referral, listing, and transplant for those with ppFEV1 of 30% or less are reported in Table 1. Similar results were seen for those with ppFEV1 of 40% or less and at least one marker of disease severity. Table 1. Odds ratios and 95% confidence intervals for lung transplantation status of people with CF with ppFEV1≤30 according to NTM species present in culture Journal of Cystic Fibrosis 22S3 (2023) S1–S408 S3
Conclusions: The presence of NTM in respiratory cultures of PwCF does not appear to decrease likelihood of transplantation referral, although a positive NTM culture was associated with lower likelihood of listing for and performance of lung transplantation. This is particularly notable for those PwCF who have had Mabsc in cultures. A limitation of this analysis is that we do not know the specific factors that decreased the probability of listing and transplantation. Additional sensitivity analyses will be conducted to include modeling to assess the effect of persistence and temporality of culture positivity as it is related to transplantation status and multivariate logistic regression evaluating interactions of other key clinical features that could affect transplant status. Whether the presence of NTM should be a factor in transplantation decisions should be determined; assessment of post-transplantation outcomes is planned. 6 Activity of cefiderocol against gram-negative bacteria isolated from people with cystic fibrosis and bronchiectasis C. McLaughlin1, J. Elborn2, C. Longshaw3,M. Tunney1. 1School of Pharmacy, Queen’s University Belfast, Belfast, UK; 2Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK; 3EU Scientific Affairs, Shionogi B.V., London, UK Background: Gram-negative pathogens causing respiratory infection are becoming progressively more resistant to conventional antibiotics such as aminoglycosides, cephalosporins, polymyxins, and carbapenems, indicating that there is a clear need for new antimicrobial agents for use in people with CF and bronchiectasis (BE). Cefiderocol is licensed for the treatment of infections due to gram-negative organisms with limited treatment options, but it has been used to treat only a small number of people with CF and BE, and data on the susceptibility of CF and BE pathogens to cefiderocol are limited. The aim of this study was to determine the susceptibility of gramnegative pathogens from CF and BE to cefiderocol and compare this with relevant comparator antibiotics. Methods: The susceptibility of 300 (CF, n = 293; BE, n = 7) gram-negative pathogens (Achromobacter spp., Pandorea spp., Ralstonia spp. Burkholderia cepacia complex, Stenotrophomonas maltophilia) to cefiderocol was determined using the Bruker UMIC cefiderocol assay, and susceptibility of 15 comparator antibiotics was determined using the Sensititre gramnegative EUMDRXXF AST plate. Minimum inhibitory concentrations (MICs) were determined using the broth microdilution method with plates read after 24 to 48 hours of incubation at 37°C. Isolates were classified as sensitive, intermediate, or resistant to each antibiotic according to EUCAST pharmacokintic/pharmacodynamic breakpoints (https://www.eucast.org/ clinical_breakpoints/). Results: The concentrations of cefiderocol required to inhibit 50% and 90% of all 300 isolates (non-species related) tested were 0.25 and 32 mg/L, respectively (Table 1), with 232 (77.3%) isolates having an MIC of 2 mg/L or less—the EUCAST pharmacokinetic/pharmacodynamic breakpoint. Cefiderocol was the only antibiotic tested that did not have an MIC90 greater than the highest concentration tested. Tigecycline also demonstrated good activity against all isolates, with an MIC50 of less than 0.5 mg/ L. The concentrations of cefiderocol required to inhibit 50% and 90% of S. maltophilia (n = 102) isolates were 0.25 and 4 mg/L, respectively, with 88 (86.2%) isolates having an MIC of 2 mg/L or less. Tigecycline also demonstrated good activity against S. maltophilia, with an MIC50 of less than 0.5 mg/L and an MIC90 of 1 mg/L. The concentrations of cefiderocol required to inhibit 50% and 90% of Achromobacterspp. isolates (n = 74) were 0.5 and 8 mg/L, respectively, with 65 (87.8%) isolates having an MIC of 2 mg/L or less. The MIC50 values for tigecycline, piperacillin/tazobactam, meropenem/vaborbactam, and ceftazidime/avibactam were in the susceptible range according to the EUCAST pharmacokintic/pharmacodynamic guidelines. The concentrations of cefiderocol required to inhibit 50% and 90%of Burkholderiaspp. (n = 106) isolates ere 0.25 and more than 32 mg/L, respectively, with 75 (70.7%) isolates having an MIC of 2 mg/L or less. The MIC50 values for ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam, and ceftolozane/tazobactam were all in the susceptible range. Table 1. In vitro activity of cefiderocol and comparator antibiotics against 300 gramnegative isolates Conclusions: Cefiderocol demonstrated good in vitro activity (MIC≤2mg/ L) against the majority of clinical isolates tested, with excellent activity apparent for Achromobacter spp. and S. maltophilia. Tigecycline also demonstrated good activity against Achromobacter spp. andS. maltophilia, with meropenem/vaborbactam demonstrating good activity against Burkholderia spp. Acknowledgements: This work was funded by Shionogi B.V. 7 Intestinal Bacteroides modulate systemic inflammation and the microbial ecology in a mouse model of cystic fibrosis: Evidence of propionate reducing inflammatory cytokines and affecting colonization R. Valls1, C. Price1,2, A. Ramsey1, N. Loeven1, J. Jones3, K. Barrack1, J. Schwartzman1, D. Royce1, R. Cramer3, J.Madan4, B. Ross3, J. Bliska1, G. O’Toole 3. 1Geisel School of Medicine, Dartmouth College, Hanover, NH; 2UMass Medical, Worcester, MA; 3Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Hanover, NH; 4Division of Child and Adolescent Psychiatry, Department of Psychiatry, Dartmouth Hitchcock Medical Center, Lebanon, NH Background: Fermentation of short chain fatty acids (SCFAs) by bacteria in the gut train and regulate the host immune system and play an important role in the physiology of these microbes. The genus Bacteroides is amajor producer of SCFAs in the gut. The presence of Bacteroides in the gut has been associated with less inflammation [1, 2]. Previous work from our lab and others has shown that infants with CF have lower levels of Bacteroides [3]. When CftrF508del mice receive intestinal supplementation with Bacteroides, systemic cytokine levels fall [4]. ABacteroides strain deficient in propionate production (Bt Δtdkprp) loses its ability to reduce IL-8 secretion in CFTR-/- Caco-2 cells, unlike a Bacteroides strain that secretes normal levels of propionate (Bt Δtdk) [4]. Methods: To investigate the role of Bacteroides-synthesized propionate in host inflammatory response, we tested whether the propionate-deficient Bt Δtdkprp would protect pathogen-free CftrF508del mice from lipopolysaccharide-induced airway inflammatory response. Stool samples were collected for 16 s amplicon sequencing. We also sent stool samples for gas chromatography–mass spectrometry to quantify SCFAs. At sac’ing, we collected serum, lung tissue, and intestinal tissue for a Luminex 32cytokine panel to understand the inflammatory response. We also dissected the intestines to collect luminal contents from across the gut that were plated on blood agar with gentamicin and grown for 48 hours in anaerobic conditions to determine the CFUs of Bacteroides, which are known to be inherently gentamicin-resistant. We completed in vitro attachment assays with Caco-2 cells and both Bacteroides strains to determine whether there were any differences in attachment and establishment of the strains on colon epithelial cells. To understand which pathways are involved in the gut-lung axis, we use LeapR. Journal of Cystic Fibrosis 22S3 (2023) S1–S408 S4
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