Eur Respir J. 2023 Oct 19;62(4):2301387. doi: 10.1183/13993003.01387-2023. Print 2023 Oct.

NO ABSTRACT

PMID:37857432 | DOI:10.1183/13993003.01387-2023

Methods Mol Biol. 2024;2725:225-237. doi: 10.1007/978-1-0716-3507-0_14.

ABSTRACT

Air-liquid interface (ALI)-cultured cells are widely used as in vitro models of the human respiratory airway in studies of pulmonary physiology, disease, and therapies. However, the primary basal cells required to establish the ALI cultures generally lose their ability to differentiate by the second or third passage, requiring a fresh batch, which can be limiting, particularly from donors with rare genotypes or in studies where gene modification or editing is required. We have developed a method that preserves the ability to expand primary cells and maintain their capacity to differentiate by lentiviral transduction with BMI1. BMI1-transduced basal airway cells are maintained in submerged culture in the same way as primary basal cells but can be passaged more than 20 times retaining their differentiation capacity in ALI cultures. BMI1-transduced basal cells can be frozen and stored long term in liquid nitrogen, enabling transfer of samples between research groups.

PMID:37856028 | DOI:10.1007/978-1-0716-3507-0_14

Int J Prev Med. 2023 Jun 22;14:83. doi: 10.4103/ijpvm.ijpvm_137_22. eCollection 2023.

ABSTRACT

BACKGROUND: Cystic fibrosis is a progressive, fatal disease affecting the quality of life. The cystic fibrosis questionnaire-revised (CFQ-R) is an efficient tool to monitor health-related quality of life in patients. The aim of this study was to explore the psychometric properties of the child and parent versions of the Persian version of the CFQ-R in the Iranian population.

METHODS: Fifty children with cystic fibrosis (6-11 years) and their parents were allocated in this methodological study to examine convergent validity, discriminant validity, test-retest reliability (n = 30), internal consistency, ceiling and floor effects, and agreement between two versions of the CFQ-R.

RESULTS: Convergent validity was confirmed for parent proxy (P < 0.05). CFQ-R discriminated patients among stages of disease severity based on lung function, age, and BMI (P < 0.05). Test-retest analysis revealed good to excellent reliability (inter-class correlation coefficient (ICC) = 0.78-0.97). In most domains, lower quality of life scores was obtained in the parent proxy compared to the child version (P < 0.05). Domain-specific correlations were found between the child version and parent proxy (P < 0.05). Internal consistency was generally confirmed (α = 0.13-0.83 in child version and α = 0.25-0.87 in parent proxy). There were no floor effects. Ceiling effects were mostly seen for physical, digestion, and body image domains in the child version and for eating, weight, and school domains in the parent proxy.

CONCLUSIONS: The child version and parent proxy of the Persian CFQ-R are valid and reliable measures and can be applied in clinical trials to monitor the quality of life in children with cystic fibrosis. It is recommended to use both versions in conjunction to better interpret the quality of life aspects of children with cystic fibrosis.

PMID:37855002 | PMC:PMC10580193 | DOI:10.4103/ijpvm.ijpvm_137_22

J Surg Case Rep. 2023 Oct 17;2023(10):rjad574. doi: 10.1093/jscr/rjad574. eCollection 2023 Oct.

ABSTRACT

Intussusception, an uncommon but potentially severe condition primarily associated with infants and young children, can also present in adults, posing distinct challenges in diagnosis and treatment. This report presents the case of a 22-year-old male with cystic fibrosis, who developed intussusception due to severe constipation in his distal gastrointestinal tract. The patient's initial presentation included abdominal pain, constipation, and abnormal laboratory results. Computed tomography scans revealed intussusception affecting the ascending colon and cecum, necessitating surgical intervention and subsequent bowel resection. In adults, the presence of intussusception often triggers suspicion of underlying pathological lead points. However, in this instance, the root cause was attributed to cystic fibrosis induced constipation. Current evidence suggests limited efficacy with conservative treatment, with bowel resection being the most definitive treatment option. Further research is warranted to establish comprehensive guidelines for managing this uncommon condition, particularly when intertwined with cystic fibrosis.

PMID:37854524 | PMC:PMC10581704 | DOI:10.1093/jscr/rjad574

Proc SPIE Int Soc Opt Eng. 2023 Feb;12463:124633Q. doi: 10.1117/12.2654343. Epub 2023 Apr 7.

ABSTRACT

Imaging is often a first-line method for diagnostics and treatment. Radiological workflows increasingly mine medical images for quantifiable features. Variability in device/vendor, acquisition protocol, data processing, etc., can dramatically affect quantitative measures, including radiomics. We recently developed a method (PixelPrint) for 3D-printing lifelike computed tomography (CT) lung phantoms, paving the way for future diagnostic imaging standardization. PixelPrint generates phantoms with accurate attenuation profiles and textures by directly translating clinical images into printer instructions that control density on a voxel-by-voxel basis. The present study introduces a library of 3D printed lung phantoms covering a wide range of lung diseases, including usual interstitial pneumonia with advanced fibrosis, chronic hypersensitivity pneumonitis, secondary tuberculosis, cystic fibrosis, Kaposi sarcoma, and pulmonary edema. CT images of the patient-based phantom are qualitatively comparable to original CT images, both in texture, resolution and contrast levels allowing for clear visualization of even subtle imaging abnormalities. The variety of cases chosen for printing include both benign and malignant pathology causing a variety of alveolar and advanced interstitial abnormalities, both clearly visualized on the phantoms. A comparison of regions of interest revealed differences in attenuation below 6 HU. Identical features on the patient and the phantom have a high degree of geometrical correlation, with differences smaller than the intrinsic spatial resolution of the scans. Using PixelPrint, it is possible to generate CT phantoms that accurately represent different pulmonary diseases and their characteristic imaging features.

PMID:37854299 | PMC:PMC10584041 | DOI:10.1117/12.2654343

Health Serv Insights. 2023 Oct 16;16:11786329231205145. doi: 10.1177/11786329231205145. eCollection 2023.

ABSTRACT

BACKGROUND: Standard of care recommend that patients with cystic fibrosis (CF) require screening investigations to assess for complications. Changing models of care due to the COVID19 pandemic may have impacted completion of recommended screening.

OBJECTIVE: To compare the frequency of screening investigations completed in people with CF before and after the onset of the COVID19 pandemic.

METHODS: Medical records were reviewed at 4 CF-specialist centers to identify screening investigations completed in the 12-months before and after pandemic onset.

RESULTS: Records of 625 patients were reviewed. Prior to pandemic onset, there was between center variability in completion of screening investigations. There was greatest baseline variation between centers in performing oral glucose tolerance test (OGTT); range 38%-69%, exercise tests; 3%-51% and sputum screening for non-tuberculous mycobacteria; 53%-81%. Following pandemic onset, blood tests, and sputum cultures were maintained at the highest rates. Exercise testing, CXR and OGTT exhibited the greatest declines, with reductions at individual centers ranging between 10%-24%, 22%-43%, and 20%-26%, respectively. Return to in-person visits following pandemic onset was variable, ranging from 16% to 74% between centers.

CONCLUSION: Completion of screening investigations varies between CF centers and changes in models of care, such as increased virtual care in response to COVID19 pandemic was associated with reduction in completion of investigations. Centers would benefit from auditing their adherence to standards of care, particularly considering recent changes in care delivery.

PMID:37854074 | PMC:PMC10580724 | DOI:10.1177/11786329231205145

Cell Rep Med. 2023 Oct 17;4(10):101210. doi: 10.1016/j.xcrm.2023.101210.

ABSTRACT

Nearly one-half of patients with cystic fibrosis (CF) carry the homozygous F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene but exhibit variable lung function phenotypes. How adaptive immunity influences their lung function remains unclear, particularly the serological antibody responses to antigens from mucoid Pseudomonas in sera from patients with CF with varying lung function. Sera from patients with CF with reduced lung function show higher anti-outer membrane protein I (OprI) immunoglobulin G1 (IgG1) titers and greater antibody-mediated complement deposition. Induction of anti-OprI antibody isotypes with complement activity enhances lung inflammation in preclinical mouse models. This enhanced inflammation is absent in immunized Rag2-/- mice and is transferrable to unimmunized mice through sera. In a CF cohort undergoing treatment with elexacaftor-tezacaftor-ivacaftor, the declination in anti-OprI IgG1 titers is associated with lung function improvement and reduced hospitalizations. These findings suggest that antibody responses to specific Pseudomonas aeruginosa (PA) antigens worsen lung function in patients with CF.

PMID:37852181 | DOI:10.1016/j.xcrm.2023.101210

Radiologie (Heidelb). 2023 Oct 18. doi: 10.1007/s00117-023-01229-1. Online ahead of print.

ABSTRACT

Due to the low proton density of the lung parenchyma and the rapid signal decay at the air-tissue interfaces, for a long time the lungs were difficult to access using magnetic resonance imaging (MRI); however, technical advances could address most of these obstacles. Pulmonary alterations associated with tissue proliferation ("plus pathologies"), can now be detected with high diagnostic accuracy because of the locally increased proton density. Compared to computed tomography (CT), MRI provides a comprehensive range of functional imaging procedures (respiratory mechanics, perfusion and ventilation). In addition, as a radiation-free noninvasive examination modality, it enables repeated examinations for assessment of the course or monitoring of the effects of treatment, even in children. This article discusses the technical aspects, gives suggestions for protocols and explains the role of MRI of the lungs in the routine assessment of various diseases.

PMID:37851088 | DOI:10.1007/s00117-023-01229-1

Front Immunol. 2023 Oct 2;14:1259004. doi: 10.3389/fimmu.2023.1259004. eCollection 2023.

ABSTRACT

Staphylococcus aureus is a common cause of hospital-acquired pneumonia associated with high mortality. Adequate clinical treatment is impeded by increasing occurrence of antibiotic resistances. Understanding the underlying mechanisms of its virulence during infections is a prerequisite to finding alternative treatments. Here, we demonstrated that an increased nuclease activity of a S. aureus isolate from a person with cystic fibrosis confers a growth advantage in a model of acute lung infection compared to the isogenic strain with low nuclease activity. Comparing these CF-isolates with a common MRSA-USA300 strain with similarly high nuclease activity but significantly elevated levels of Staphylococcal Protein A (SpA) revealed that infection with USA300 resulted in a significantly increased bacterial burden in a model of murine lung infection. Replenishment with the cell wall-bound SpA of S. aureus, which can also be secreted into the environment and binds to tumor necrosis factor receptor -1 (TNFR-1) to the CF-isolates abrogated these differences. In vitro experiments confirmed significant differences in spa-expression between USA300 compared to CF-isolates, thereby influencing TNFR-1 shedding, L-selectin shedding, and production of reactive oxygen species through activation of ADAM17.

PMID:37849760 | PMC:PMC10577289 | DOI:10.3389/fimmu.2023.1259004

BME Front. 2023 Mar 31;4:0016. doi: 10.34133/bmef.0016. eCollection 2023.

ABSTRACT

The effective treatment of patients with cancer hinges on the delivery of therapeutics to a tumor site. Nanoparticles provide an essential transport system. We present 5 principles to consider when designing nanoparticles for cancer targeting: (a) Nanoparticles acquire biological identity in vivo, (b) organs compete for nanoparticles in circulation, (c) nanoparticles must enter solid tumors to target tumor components, (d) nanoparticles must navigate the tumor microenvironment for cellular or organelle targeting, and (e) size, shape, surface chemistry, and other physicochemical properties of nanoparticles influence their transport process to the target. This review article describes these principles and their application for engineering nanoparticle delivery systems to carry therapeutics to tumors or other disease targets.

PMID:37849661 | PMC:PMC10085247 | DOI:10.34133/bmef.0016

ACS Med Chem Lett. 2023 Sep 20;14(10):1338-1343. doi: 10.1021/acsmedchemlett.3c00155. eCollection 2023 Oct 12.

ABSTRACT

Cystic fibrosis (CF) is an autosomal genetic disorder caused by disrupted anion transport in epithelial cells lining tissues in the human airways and digestive system. While cystic fibrosis transmembrane conductance regulator (CFTR) modulator compounds have provided transformative improvement in CF respiratory function, certain patients exhibit marginal clinical benefit or detrimental effects or have a form of the disease not approved or unlikely to respond using CFTR modulation. We tested hit compounds from a 300,000-drug screen for their ability to augment CFTR transepithelial transport alone or in combination with the FDA-approved CFTR potentiator ivacaftor (VX-770). A subsequent SAR campaign led us to a class of 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines that in combination with VX-770 rescued function of G551D mutant CFTR channels to approximately 400% above the activity of VX-770 alone and to nearly wild-type CFTR levels in the same Fischer rat thyroid model system.

PMID:37849531 | PMC:PMC10577695 | DOI:10.1021/acsmedchemlett.3c00155

Am J Physiol Lung Cell Mol Physiol. 2023 Oct 17. doi: 10.1152/ajplung.00390.2022. Online ahead of print.

ABSTRACT

Airway mucociliary clearance (MCC) is required for host defense and is often diminished in chronic lung diseases. Effective clearance depends upon coordinated actions of the airway epithelium and a mobile mucus layer. Dysregulation of the primary secreted airway mucin proteins, MUC5B and MUC5AC, is associated with a reduction in the rate of MCC; however, how other secreted proteins impact the integrity of the mucus layer and MCC remains unclear. We previously identified the gene Bpifb1/Lplunc1 as a regulator of airway MUC5B protein levels using genetic approaches. Here, we show that BPIFB1 is required for effective MCC in vivo using Bpifb1 knockout (KO) mice. Reduced MCC in Bpifb1 KO mice occurred in the absence of defects in epithelial ion transport or reduced ciliary beat frequency. Loss of BPIFB1 in vivo and in vitro altered biophysical and biochemical properties of mucus that have been previously linked to impaired MCC. Finally, we detected colocalization of BPIFB1 and MUC5B in secretory granules in mice and in the protein mesh of secreted mucus in human airway epithelia cultures. Collectively, our findings demonstrate that BPIFB1 is an important component of the mucociliary apparatus in mice and a key component of the mucus protein network.

PMID:37847709 | DOI:10.1152/ajplung.00390.2022

mBio. 2023 Oct 17:e0150623. doi: 10.1128/mbio.01506-23. Online ahead of print.

ABSTRACT

Antibiotic resistance is a continuing global health crisis. Identifying the evolutionary trajectories leading to increased antimicrobial resistance can be critical to the discovery of biomarkers for clinical diagnostics and new targets for drug discovery. While the combination of patient data and in vitro experimental evolution has been remarkably successful in extending our understanding of antimicrobial resistance, it can be difficult for in vitro methods to recapitulate the spatial structure and consequent microenvironments that characterize in vivo infection. Notably, in cystic fibrosis (CF) patients, changes to either the PmrA/PmrB or PhoP/PhoQ two-component systems have been identified as critical drivers for high levels of colistin and polymyxin resistance. When using microfluidic emulsions to provide spatially structured, low-competition environments, we found that adaptive mutations to phoQ were more successful than pmrB in increasing colistin resistance. Conversely, mutations to pmrB were readily identified using well-mixed unstructured cultures. We found that oxygen concentration gradients within the microdroplet emulsions favored adaptive changes to the PhoP/PhoQ pathway consistent with microaerobic conditions that can be found in the lungs of CF patients. We also observed mutations linked to hallmark adaptations to the CF lung environment, such as loss of motility and loss of O antigen biosynthesis (wbpL). Mutation to wbpL, in addition to causing loss of O antigen, was additionally shown to confer moderately increased colistin resistance. Taken together, our data suggest that distinct evolutionary trajectories to colistin resistance may be shaped by the microaerobic partitioning and spatial separation imposed within the CF lung.IMPORTANCEAntibiotic resistance remains one of the great challenges confronting public health in the world today. Individuals with compromised immune systems or underlying health conditions are often at an increased for bacterial infections. Patients with cystic fibrosis (CF) produce thick mucus that clogs airways and provides a very favorable environment for infection by bacteria that further decrease lung function and, ultimately, mortality. CF patients are often infected by bacteria such as Pseudomonas aeruginosa early in life and experience a series of chronic infections that, over time, become increasingly difficult to treat due to increased antibiotic resistance. Colistin is a major antibiotic used to treat CF patients. Clinical and laboratory studies have identified PmrA/PmrB and PhoP/PhoQ as responsible for increased resistance to colistin. Both have been identified in CF patient lungs, but why, in some cases, is it one and not the other? In this study, we show that distinct evolutionary trajectories to colistin resistance may be favored by the microaerobic partitioning found within the damaged CF lung.

PMID:37847036 | DOI:10.1128/mbio.01506-23

Infect Immun. 2023 Oct 17:e0024023. doi: 10.1128/iai.00240-23. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a human genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene that encodes a chloride channel. The most severe clinical manifestation is associated with chronic pulmonary infections by pathogenic and opportunistic microbes. Drosophila melanogaster has become the invertebrate model of choice for modeling microbial infections and studying the induced innate immune response. Here, we review its contribution to the understanding of infections with six major pathogens associated with CF (Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia, Mycobacterium abscessus, Streptococcus pneumoniae, and Aspergillus fumigatus) together with the perspectives opened by the recent availability of two CF models in this model organism.

PMID:37847031 | DOI:10.1128/iai.00240-23

Epidemiol Prev. 2023 Jul-Oct;47(4-5):243-256. doi: 10.19191/EP23.4-5.A612.064.

ABSTRACT

BACKGROUND: genetic testing for cystic fibrosis (CF) has been offered to people with higher risk of being carrier.

OBJECTIVES: to assess the effectiveness of population-based CF carrier screening for adults of reproductive age and its optimal organizational features.

DESIGN: systematic review.

SETTING AND PARTICIPANTS: MedLine, Embase, Cochrane Library, CINAHL and LILACS (1990-2022) were searched to retrieve primary and secondary studies on adults (16 years and older), with no clinical indication or genetic risk, eligible for genetic testing for CF carrier status.

MAIN OUTCOMES MEASURES: attitude to screening, uptake of screening offered, informed reproductive choices.

RESULTS: a total of 3,326 records were screened and 292 potentially eligible full-text publications assessed. The review included 71 publications, corresponding to 3 reviews, 40 cohort studies (11 comparative, 29 single-arm), and 6 model studies, published between 1992 and 2021 (median 1998). Only one study compared screening or no screening. This study suggested an association between carrier screening and a lower incidence of CF. Comparative studies examined different approaches for invitation and testing, i.e., settings, target population (individuals/couples, prenatal/preconceptional), how invitations are organized (primary care/maternal hospitals), and format and content of the pre-test information. However, no firm conclusions can be drawn on the impact of these features on informed reproductive choices, uptake, and attitude, because of the limitations of the evidence collected.

CONCLUSIONS: the broad heterogeneity of the studies, methodological weaknesses, and the limited transferability of the results mean there is still uncertainty about the effectiveness of preconceptional and prenatal CF carrier screening in the general population.

PMID:37846447 | DOI:10.19191/EP23.4-5.A612.064

J Pharm Sci. 2023 Oct 14:S0022-3549(23)00424-0. doi: 10.1016/j.xphs.2023.10.016. Online ahead of print.

ABSTRACT

This review will highlight portions of Dr. William Jusko's and colleagues' work that affected the clinical use and study of corticosteroids in acute and chronic disease management. Selected publications related to corticosteroid pharmacokinetics and pharmacodynamics from the 1970s through today were included in this review, with a focus on the foundational human-based studies conducted in the 1970s-1990s. Dr. Jusko contributed significantly to early corticosteroid pharmacology across several domains including: 1) foundational corticosteroid pharmacokinetic methods and parameter development, 2) disease state-variation in corticosteroid pharmacokinetics, 3) drug interaction effects on corticosteroid pharmacokinetics, and 4) early corticosteroid pharmacodynamic studies. In an era where little was known about the pharmacokinetics and pharmacodynamics of corticosteroids, Dr. Jusko's work opened the eyes of researchers and clinicians to the potential for disease and drug interactions that could reduce or enhance the effects of corticosteroids. This significant body of work paved the way for alternative routes of administration that would be useful in concentrating the activity at the site of action and markedly reduced systemic drug exposure, minimizing the risk of adverse effects through application of the dose-sparing pharmacokinetic and pharmacodynamic principles.

PMID:37844761 | DOI:10.1016/j.xphs.2023.10.016

J Cyst Fibros. 2023 Oct 14:S1569-1993(23)00931-1. doi: 10.1016/j.jcf.2023.10.010. Online ahead of print.

ABSTRACT

BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (E/T/I) is highly effective clinically for those with at least one F508del-CFTR allele. The effects of E/T/I on mucociliary clearance (MCC) and sputum properties are unknown. We, therefore, sought to characterize the effects of E/T/I on in vivo MCC and sputum characteristics hypothesized to impact mucus transport.

METHODS: Forty-four participants ≥12 years of age were enrolled into this prospective, observational trial prior to initiation of E/T/I and had baseline measurement of MCC and characterization of induced sputum and exhaled breath condensate (EBC) samples. Study procedures were repeated after 1 month of E/T/I treatment.

RESULTS: Average age was 27.7 years with baseline forced expiratory volume in 1 second (FEV1) of 78.2 % predicted. 52 % of subjects had previously been treated with a 2-drug CFTR modulator combination. The average whole lung MCC rate measured over 60 min (WLAveClr60) significantly improved from baseline to post-E/T/I (14.8 vs. 22.8 %; p = 0.0002), as did other MCC indices. Sputum% solids also improved (modeled mean 3.4 vs. 2.2 %; p<0.0001), whereas non-significant reductions in sputum macrorheology (G', G") were observed. No meaningful changes in exhaled breath condensate endpoints (sialic acid:urea ratio, pH) were observed.

CONCLUSIONS: E/T/I improved the hydration of respiratory secretions (% solids) and markedly accelerated MCC. These data confirm the link between CFTR function, mucus solid content, and MCC and help to define the utility of MCC and mucus-related bioassays in future efforts to restore CFTR function in all people with CF.

PMID:37845149 | DOI:10.1016/j.jcf.2023.10.010

J Clin Invest. 2023 Oct 16;133(20):e174667. doi: 10.1172/JCI174667.

ABSTRACT

In the lungs, the cystic fibrosis transmembrane conductance regulator (CFTR) regulates ion transport in surface-airway epithelia and submucosal glands, thus determining airway surface liquid (ASL) volume and mucus hydration. In this issue of the JCI, Lei Lei and colleagues report that the CFTR-rich and barttin/Cl- channel-expressing ionocytes mediate chloride absorption across airway epithelia, whereas the more abundant basal cells and secretory cells mediate chloride secretion. Thus, CFTR-mediated secretion and absorption of chloride ions in the lung are segregated by cell type, which has implications for future molecular therapies for cystic fibrosis lung disease.

PMID:37843282 | DOI:10.1172/JCI174667

Clin Infect Dis. 2023 Oct 16;77(Supplement_4):S279-S287. doi: 10.1093/cid/ciad475.

ABSTRACT

In this overview, we describe important contributions from the Antibacterial Resistance Leadership Group (ARLG) to patient care, clinical trials design, and mentorship while outlining future priorities. The ARLG research agenda is focused on 3 key areas: gram-positive infections, gram-negative infections, and diagnostics. The ARLG has developed an innovative approach to clinical trials design, the desirability of outcome ranking (DOOR), which uses an ordinal measure of global outcome to assess both benefits and harms. DOOR was initially applied to observational studies to determine optimal dosing of vancomycin for methicillin-resistant Staphylcococcus aureus bacteremia and the efficacy of ceftazidime-avibactam versus colistin for the treatment of carbapenem-resistant Enterobacterales infection. DOOR is being successfully applied to the analysis of interventional trials and, in collaboration with the US Food and Drug Administration (FDA), for use in registrational trials. In the area of diagnostics, the ARLG developed Master Protocol for Evaluating Multiple Infection Diagnostics (MASTERMIND), an innovative design that allows simultaneous testing of multiple diagnostic platforms in a single study. This approach will be used to compare molecular assays for the identification of fluoroquinolone-resistant Neisseria gonorrhoeae (MASTER GC) and to compare rapid diagnostic tests for bloodstream infections. The ARLG has initiated a first-in-kind randomized, double-blind, placebo-controlled trial in participants with cystic fibrosis who are chronically colonized with Pseudomonas aeruginosa to assess the pharmacokinetics and antimicrobial activity of bacteriophage therapy. Finally, an engaged and highly trained workforce is critical for continued and future success against antimicrobial drug resistance. Thus, the ARLG has developed a robust mentoring program targeted to each stage of research training to attract and retain investigators in the field of antimicrobial resistance research.

PMID:37843121 | DOI:10.1093/cid/ciad475

Clin Infect Dis. 2023 Oct 16;77(Supplement_4):S305-S313. doi: 10.1093/cid/ciad547.

ABSTRACT

Addressing the treatment and prevention of antibacterial-resistant gram-negative bacterial infections is a priority area of the Antibacterial Resistance Leadership Group (ARLG). The ARLG has conducted a series of observational studies to define the clinical and molecular global epidemiology of carbapenem-resistant and ceftriaxone-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii, with the goal of optimizing the design and execution of interventional studies. One ongoing ARLG study aims to better understand the impact of fluoroquinolone-resistant gram-negative gut bacteria in neutropenic patients, which threatens to undermine the effectiveness of fluoroquinolone prophylaxis in these vulnerable patients. The ARLG has conducted pharmacokinetic studies to inform the optimal dosing of antibiotics that are important in the treatment of drug-resistant gram-negative bacteria, including oral fosfomycin, intravenous minocycline, and a combination of intravenous ceftazidime-avibactam and aztreonam. In addition, randomized clinical trials have assessed the safety and efficacy of step-down oral fosfomycin for complicated urinary tract infections and single-dose intravenous phage therapy for adult patients with cystic fibrosis who are chronically colonized with P. aeruginosa in their respiratory tract. Thus, the focus of investigation in the ARLG has evolved from improving understanding of drug-resistant gram-negative bacterial infections to positively affecting clinical care for affected patients through a combination of interventional pharmacokinetic and clinical studies, a focus that will be maintained moving forward.

PMID:37843118 | DOI:10.1093/cid/ciad547