Microbiol Spectr. 2023 Dec 5:e0351123. doi: 10.1128/spectrum.03511-23. Online ahead of print.

ABSTRACT

Microbes produce a large array of extracellular molecules, which serve as signals and cues to promote polymicrobial interactions and alter the function of microbial communities. This has been particularly well studied in the human oral microbiome, where key metabolites have been shown to impact both health and disease. Here, we used an untargeted mass spectrometry approach to comprehensively assess the extracellular metabolome of the pathogen Aggregatibacter actinomycetemcomitans and the commensal Streptococcus gordonii during mono- and co-culture. We generated and made publicly available a metabolomic data set that includes hundreds of potential metabolites and leveraged this data set to identify an operon important for glutathione secretion in A. actinomycetemcomitans.

PMID:38051055 | DOI:10.1128/spectrum.03511-23

Pediatr Pulmonol. 2023 Dec 5. doi: 10.1002/ppul.26798. Online ahead of print.

ABSTRACT

INTRODUCTION: People with cystic fibrosis (pwCF) require a multidisciplinary care team due to disease complexity. The Cystic Fibrosis Foundation (CFF) notes that pharmacists are recommended, while other organizations consider pharmacists required. In 2016, the CFF initiated a grant program for CFF-accredited care centers and affiliate programs (CFF-ACCAP) to implement outpatient pharmacy services. The primary objective of this study was to compare surveys regarding pharmacy involvement in CFF-ACCAP pre- and post-grant implementation.

METHODS: This was an IRB-approved, survey-based study. The surveys were distributed via the CF pharmacist-pharmacy technician and center director e-mail exchanges.

RESULTS: There are currently 244 CFF-ACCAP and 158 pharmacists. Forty-two pharmacists completed the 2013 survey and 77 completed the 2023 survey. Practice site shifted from primarily the inpatient (58.5%) to outpatient settings (67.5%; p < .001). Most positions were created in the past 7 years (81%) with 50% currently or previously funded by the CFF grant program. CFF center director response decreased from 2013 to 2023 (106 vs. 48) but centers with a dedicated CF pharmacist increased from 2013 to 2023 (66%-86%; p = .014). In the 2023 survey, we received responses from 17 pharmacy technicians, who were newly included. Most of these technicians (64%) reported working in outpatient clinics.

CONCLUSIONS: Since 2013, pharmacy presence has grown at CFF-ACCAP, partly due to the CFF grant program. Despite pharmacists not being required members of the multidisciplinary care team, their presence is notable in 65% of CFF-ACCAP centers, where they contribute significantly to improving the care provided for pwCF.

PMID:38050809 | DOI:10.1002/ppul.26798

Eur J Pharm Biopharm. 2023 Dec 2:S0939-6411(23)00321-1. doi: 10.1016/j.ejpb.2023.12.001. Online ahead of print.

ABSTRACT

Mucus is a complex polymeric hydrogel that serves as a critical defense in several organs. In the lungs, it provides a formidable barrier against inhaled particles such as microorganisms. In addition, mucus is essential for normal lung physiology, as it promotes immune tolerance and facilitates a normal commensal pulmonary microbiome. Hypersecretion of airway mucus is a characteristic of numerous respiratory diseases, such as Chronic Obstructive Pulmonary Disease (COPD) and Cystic Fibrosis (CF), and creates pulmonary obstruction, limiting the effectiveness of inhaled therapies. Due to those alterations, therapeutic strategies must be optimal to limit airway obstruction and restore pulmonary function. Mucoactive drugs are common therapeutic options and are classified into different groups depending on their modes of action, i.e., expectorants, mucokinetics, mucoregulators and mucolytics. This review focuses on mucoactive drugs and their modes of action. A special focus will be made on two challenging pulmonary pathologies: COPD and CF, and on their clinical studies conducted with mucoactive drugs.

PMID:38048888 | DOI:10.1016/j.ejpb.2023.12.001

Cell Biochem Biophys. 2023 Dec 4. doi: 10.1007/s12013-023-01200-w. Online ahead of print.

ABSTRACT

Cystic fibrosis is a genetic disorder inherited in an autosomal recessive manner. It is caused by a mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene on chromosome 7, which leads to abnormal regulation of chloride and bicarbonate ions in cells that line organs like the lungs and pancreas. The CFTR protein plays a crucial role in regulating chloride ion flow, and its absence or malfunction causes the production of thick mucus that affects several organs. There are more than 2000 identified mutations that are classified into seven categories based on their dysfunction mechanisms. In this article, we have conducted a thorough examination and consolidation of the diverse array of tests essential for the quantification of CFTR functionality. Furthermore, we have engaged in a comprehensive discourse regarding the recent advancements in CFTR modulator therapy, a pivotal approach utilized for the management of cystic fibrosis, alongside its concomitant relevance in evaluating CFTR functionality.

PMID:38048024 | DOI:10.1007/s12013-023-01200-w

JAC Antimicrob Resist. 2023 Dec 1;5(6):dlad129. doi: 10.1093/jacamr/dlad129. eCollection 2023 Dec.

ABSTRACT

BACKGROUND: Antibiotic adherence is poor amongst people with cystic fibrosis (CF). Low-quality patient information leaflets (PILs), which accompany prescription antibiotics, with poor readability may contribute to poor antibiotic adherence, with the potential for antimicrobial resistance (AMR) development. The aim of this study was to examine the readability of antibiotic PILs used to treat CF lung infections.

METHODS: CF-related antibiotics (n = 23; seven classes: aminoglycosides, β-lactams, fluoroquinolones, macrolides/lincosamides, oxazolidinones, tetracyclines, trimethoprim/sulfamethoxazole) were investigated. Readability of PILs (n = 141; 23 antibiotics) from the EU (n = 40), USA (n = 42) and UK (n = 59) was calculated.

RESULTS: Mean [± standard error of mean (SEM)] values for the Flesch Reading Ease (FRE) for EU, USA and UK were 50.0 ± 1.1, 56.2 ± 1.3 and 51.7 ± 1.1, respectively (FRE target ≥60). Mean (± SEM) values for the Flesch Kinkaid Grade Level (FKGL) for the EU, USA and UK were 9.0 ± 0.2, 7.5 ± 0.2 and 9.6 ± 0.2, respectively (FKGL target ≤8). US PILs were significantly shorter (P < 0.0001) in words (mean ± SEM = 1365 ± 52), than either UK or EU PILs, with fewer sentences (P < 0.0001), fewer words per sentence (P < 0.0001) and fewer syllables per word. The mean ( ± SEM) reading time of UK PILs (n = 59) was 12.7 ± 0.55 mins .

CONCLUSIONS: Readability of antibiotic PILs is poor. Improving PIL readability may lead to improved health literacy, which may translate to increased antibiotic adherence and AMR avoidance. Authors preparing written materials for the lay/patient CF community are encouraged to employ readability calculators, so that final materials are within recommended readability reference parameters, to support the health (antibiotic) literacy of their readers.

PMID:38046567 | PMC:PMC10691746 | DOI:10.1093/jacamr/dlad129

Evol Lett. 2023 Sep 20;7(6):389-400. doi: 10.1093/evlett/qrad034. eCollection 2023 Dec.

ABSTRACT

Pathogenic bacteria respond to antibiotic pressure with the evolution of resistance but survival can also depend on their ability to tolerate antibiotic treatment, known as tolerance. While a variety of resistance mechanisms and underlying genetics are well characterized in vitro and in vivo, an understanding of the evolution of tolerance, and how it interacts with resistance in situ is lacking. We assayed for tolerance and resistance in isolates of Pseudomonas aeruginosa from chronic cystic fibrosis lung infections spanning up to 40 years of evolution, with 3 clinically relevant antibiotics: meropenem, ciprofloxacin, and tobramycin. We present evidence that tolerance is under positive selection in the lung and that it can act as an evolutionary stepping stone to resistance. However, by examining evolutionary patterns across multiple patients in different clone types, a key result is that the potential for an association between the evolution of resistance and tolerance is not inevitable, and difficult to predict.

PMID:38045720 | PMC:PMC10693005 | DOI:10.1093/evlett/qrad034

bioRxiv. 2023 Nov 21:2023.11.20.567244. doi: 10.1101/2023.11.20.567244. Preprint.

ABSTRACT

The mucus lining of the human airway epithelium contains two gel-forming mucins, MUC5B and MUC5AC. During progression of cystic fibrosis (CF), mucus hyper-concentrates as its mucin ratio changes, coinciding with formation of insoluble, dense mucus flakes. We explore rheological heterogeneity of this pathology with reconstituted mucus matching three stages of CF progression and particle-tracking of 200 nm and 1 micron diameter beads. We introduce statistical data analysis methods specific to low signal-to-noise data within flakes. Each bead time series is decomposed into: (i) a fractional Brownian motion (fBm) classifier of the pure time-series signal ; (ii) high-frequency static and dynamic noise; and (iii) low-frequency deterministic drift. Subsequent analysis focuses on the denoised fBm classifier ensemble from each mucus sample and bead diameter. Every ensemble fails a homogeneity test, compelling clustering methods to assess levels of heterogeneity. The first binary level detects beads within vs. outside flakes. A second binary level detects within-flake bead signals that can vs. cannot be disentangled from the experimental noise floor. We show all denoised ensembles, within- and outside-flakes, fail a homogeneity test, compelling additional clustering; next, all clusters with sufficient data fail a homogeneity test. These levels of heterogeneity are consistent with outcomes from a stochastic phase-separation process, and dictate applying the generalized Stokes-Einstein relation to each bead per cluster per sample, then frequency-domain averaging to assess rheological heterogeneity. Flakes exhibit a spectrum of gel-like and sol-like domains, outside-flake solutions a spectrum of sol-like domains, painting a rheological signature of the phase-separation process underlying flake-burdened mucus.

PMID:38045262 | PMC:PMC10690152 | DOI:10.1101/2023.11.20.567244

Heliyon. 2023 Nov 13;9(11):e22281. doi: 10.1016/j.heliyon.2023.e22281. eCollection 2023 Nov.

ABSTRACT

BACKGROUND: CFTR nonsense alleles generate negligible CFTR protein due to the nonsense mutation: 1) triggering CFTR mRNA degradation by nonsense-mediated mRNA decay (NMD), and 2) terminating CFTR mRNA translation prematurely. Thus, people with cystic fibrosis (PwCF) who carry nonsense alleles cannot benefit from current modulator drugs, which target CFTR protein. In this study, we examined whether PTBP1 and HNRNPL, two RNA binding proteins that protect a subset of mRNAs with a long 3' untranslated region (UTR) from NMD, similarly affect CFTR mRNA.Silencing RNAs were used to deplete PTBP1 or HNRNPL in 16HBE14o- human bronchial epithelial cells expressing WT, G542X, or W1282X CFTR. CFTR mRNA abundance was measured relative to controls by quantitative PCR. PTBP1 and HNRNPL were also exogenously expressed in each cell line and CFTR mRNA levels were similarly quantified.

RESULTS: PTBP1 depletion reduced CFTR mRNA abundance in all three 16HBE14o- cell lines; HRNPL depletion reduced CFTR mRNA abundance in only the G542X and W1282X cell lines. Notably, decreased CFTR mRNA abundance correlated with increased mRNA decay. Exogenous expression of PTBP1 or HNRNPL increased CFTR mRNA abundance in all three cell lines; HNRNPL overexpression generally increased CFTR to a greater extent in G542X and W1282X 16HBE14o- cells.Our data indicate that PTBP1 and HNRNPL regulate CFTR mRNA abundance by protecting CFTR transcripts from NMD. This suggests that PTBP1 and/or HNRNPL may represent potential therapeutic targets to increase CFTR mRNA abundance and enhance responses to CFTR modulators and other therapeutic approaches in PwCF.

PMID:38045134 | PMC:PMC10692906 | DOI:10.1016/j.heliyon.2023.e22281

Front Microbiol. 2023 Nov 17;14:1290952. doi: 10.3389/fmicb.2023.1290952. eCollection 2023.

ABSTRACT

The purpose of the work was to investigate the impact of sodium chloride (NaCl) on the antimicrobial efficacy of ceragenins (CSAs) and antimicrobial peptides (AMPs) against bacterial and fungal pathogens associated with cystic fibrosis (CF) lung infections. CF-associated bacterial (Pseudomonas aeruginosa, Ochrobactrum spp., and Staphylococcus aureus), and fungal pathogens (Candida albicans, and Candida tropicalis) were used as target organisms for ceragenins (CSA-13 and CSA-131) and AMPs (LL-37 and omiganan). Susceptibility to the tested compounds was assessed using minimal inhibitory concentrations (MICs) and bactericidal concentrations (MBCs), as well as by colony counting assays in CF sputum samples supplemented with various concentrations of NaCl. Our results demonstrated that ceragenins exhibit potent antimicrobial activity in CF sputum regardless of the NaCl concentration when compared to LL-37 and omiganan. Given the broad-spectrum antimicrobial activity of ceragenins in the microenvironments mimicking the airways of CF patients, ceragenins might be promising agents in managing CF disease.

PMID:38045035 | PMC:PMC10693459 | DOI:10.3389/fmicb.2023.1290952

J Cyst Fibros. 2023 Dec 2:S1569-1993(23)01722-8. doi: 10.1016/j.jcf.2023.11.014. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) contributes a significant economic burden on individuals, healthcare systems, and society. Understanding the economic impact of CF is crucial for planning resource allocation.

METHODS: We conducted a scoping review of literature published between 1990 and 2022 that reported the cost of illness, and/or economic burden of CF. Costs were adjusted for inflation and reported as United States dollars.

RESULTS: A total of 39 studies were included. Direct healthcare costs (e.g., medications, inpatient and outpatient care) were the most frequently reported. Most studies estimated the cost of CF using a prevalence-based (n = 18, 46.2 %), bottom-up approach (n = 23, 59 %). Direct non-healthcare costs and indirect costs were seldom included. The most frequently reported direct cost components were medications (n = 34, 87.2 %), inpatient care (n = 33, 84.6 %), and outpatient care (n = 31, 79.5 %). Twenty-eight percent (n = 11) of studies reported the burden of CF from all three perspectives (healthcare system (payer), individual, and society). Indirect costs of CF were reported in approximately 20 % of studies (n = 8). The reported total cost of CF varied widely, ranging from $451 to $160,000 per person per year (2022 US$). The total cost depended on the number of domains and perspectives included in each study.

CONCLUSIONS: Most studies only reported costs to the healthcare system (i.e., hospitalizations and healthcare encounters) which likely underestimates the total costs of CF. The wide range of costs reported highlights the importance of standardizing perspectives, domains and costs when estimating the economic burden of CF.

PMID:38044160 | DOI:10.1016/j.jcf.2023.11.014

Nat Commun. 2023 Dec 2;14(1):7986. doi: 10.1038/s41467-023-43702-4.

ABSTRACT

Quorum sensing is a mechanism of bacterial communication that controls virulence gene expression. Pseudomonas aeruginosa regulates virulence via two synthase/transcription factor receptor pairs: LasI/R and RhlI/R. LasR is considered the master transcriptional regulator of quorum sensing, as it upregulates rhlI/R. However, clinical isolates often have inactivating mutations in lasR, while maintaining Rhl-dependent signaling. We sought to understand how quorum sensing progresses in isolates with lasR mutations, specifically via activation of RhlR. We find that clinical isolates with lasR inactivating mutations often harbor concurrent mutations in rhlI. Using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry, we discover that strains lacking lasR overproduce the RhlI-synthesized autoinducer and that RhlI variants re-calibrate autoinducer concentrations to wild-type levels, restoring virulent phenotypes. These findings provide a mechanism for the plasticity of quorum sensing progression in an acute infection niche.

PMID:38042853 | DOI:10.1038/s41467-023-43702-4

J Cyst Fibros. 2023 Dec 1:S1569-1993(23)00130-3. doi: 10.1016/j.jcf.2023.04.024. Online ahead of print.

ABSTRACT

BACKGROUND: Patient-centred trial design optimises recruitment and retention, reduces trial failure rates and increases the diversity of trial cohorts. This allows safe and effective treatments to reach clinic more quickly. To achieve this, patients' views must be incorporated into trial design.

METHODS: A discrete choice experiment was used to quantify preferences of pwCF for trials features; medicine type, trial location, stipend, washout, drug access on trial completion and trial design. Respondents were presented pairs of hypothetical trial scenarios with different level combinations assigned through experimental design. Respondents were asked to pick their preferred option or decline both. The cross-sectional data were explored using a Random Parameters Logit model.

RESULTS: We received 207 eligible responses between Oct2020-Jan2021. The strongest influence on the decision to participate was trial location; pwCF favour participation at their usual clinical centre. Greater travel distances made respondents less willing to participate. Post-trial drug access ranked second. pwCF would rather participate in modulator trials than trials of other drugs. In general, pwCF did not favour a washout period, but were more prepared to washout non-modulators than modulators. Stipend provision was not ranked highly, but higher stipends increased intention to participate. Trial design (placebo vs open-label) had minimal influence on the decision to participate. There are complex interactions between placebos and washouts.

CONCLUSIONS: We used quantitative methods to systematically elicit preferences of pwCF for clinical trials' features. We explore the relevance of our findings to trial design and delivery in the current CF trials landscape.

PMID:38042750 | DOI:10.1016/j.jcf.2023.04.024

Clin Ther. 2023 Dec 1:S0149-2918(23)00433-2. doi: 10.1016/j.clinthera.2023.11.003. Online ahead of print.

ABSTRACT

PURPOSE: Cystic fibrosis (CF) is a monogenetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein and affecting multiple organs, including the lungs and liver. Almost 90% of people affected carry at least 1 Phe508del CFTR mutation. Medical treatment with the CFTR-modulating drug elexacaftor-tezacaftor-ivacaftor (ETI) has been proven to be efficacious in carriers of at least 1 Phe508del CFTR mutation. Use of ETI in patients with CF (pwCF) and liver cirrhosis is still controversial. Therefore, stepwise introduction of ETI in pwCF and liver cirrhosis Child-Pugh A or B was evaluated using clinical and therapeutic drug monitoring.

METHODS: Seven consecutive pwCF received ETI. Four dosing steps were defined, at each of which the patients underwent clinical examination, routine blood tests, and therapeutic drug monitoring. Exposure of elexacaftor, tezacaftor, and ivacaftor was assessed by means of determination of AUC.

FINDINGS: ETI was successfully introduced and maintained in all pwCF. In those with Child-Pugh B cirrhosis (n = 2), diminishment of the dose as recommended by the label resulted in AUC values that were lower than the mean AUC values in pwCF without hepatic impairment, as reported previously.

IMPLICATIONS: Despite the limitations of this small case series, stepwise elevation of ETI dose did not induce clinical adverse effects or increases in serum liver test results under strict clinical follow-up and therapeutic drug monitoring, and may allow tolerable introduction of this therapy in pwCF and cirrhosis Child-Pugh A and possibly B.

PMID:38042631 | DOI:10.1016/j.clinthera.2023.11.003

Adv Drug Deliv Rev. 2023 Nov 29:115146. doi: 10.1016/j.addr.2023.115146. Online ahead of print.

ABSTRACT

Inhaled medicines continue to be an essential part of treatment for respiratory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. In addition, inhalation technology, which is an active area of research and innovation to deliver medications via the lung to the bloodstream, offers potential advantages such as rapid onset of action, enhanced bioavailability, and reduced side effects for local treatments. Certain inhaled macromolecules and particles can also end up in different organs via lymphatic transport from the respiratory epithelium. While the majority of research on inhaled medicines is focused on the delivery technology, particle engineering, combination therapies, innovations in inhaler devices, and digital health technologies, researchers are also exploring new pharmaceutical technologies and strategies to prolong the duration of action of inhaled drugs. This is because, in contrast to most inhaled medicines that exert a rapid onset and short duration of action, long-acting inhaled medicines (LAIM) improve not only improve patient compliance by reducing the dosing frequency, but also the effectiveness and convenience of inhaled therapies to better manage patients' conditions. This paper reviews the advances in LAIM, the pharmaceutical technologies and strategies for developing LAIM, and emerging new inhaled modalities that possess a long-acting nature and potential in the treatment and prevention of various diseases. The challenges in the development of the future LAIM are also discussed where active research and innovations are taking place.

PMID:38040120 | DOI:10.1016/j.addr.2023.115146

Cytokine. 2023 Nov 29;173:156452. doi: 10.1016/j.cyto.2023.156452. Online ahead of print.

ABSTRACT

BACKGROUND: Obesity is known to be a pro-inflammatory condition affecting multiple organs. Obesity as a systemic pro-inflammatory state, might be associated with bronchial inflammation in non-smoking adolescents with a BMI ≥ 30 kg/m2 without evidence of concomitant chronic diseases.

MATERIALS AND METHODS: We studied non-asthmatic obese patients (n = 20; median age 15.8 years; BMI 35.0 kg/m2) compared to age matched healthy control subjects (n = 20; median age 17.5 years; BMI 21.5 kg/m2). Induced sputum differential cell counts and sputum mRNA levels were assessed for all study subjects. Serum levels of CRP, IL-6, and IL-8 were measured. Further, IL-5, IL-6, IL-8, IL-13, IL-17, TNF-α, IFN-γ, and IP-10 protein levels were analyzed in induced sputum was.

RESULTS: Serum CRP levels, sputum inflammatory cell load and sputum eosinophils differed significantly between obese and non-obese subjects, for sputum neutrophils, a correlation was shown with BMI ≥ 30 kg/m2. Differences were also observed for sputum mRNA expression of IL6, IL8, IL13, IL17, IL23, and IFN-γ, as well as the transcription factors T-bet, GATA3, and FoxP3.

CONCLUSIONS: Increased bronchial inflammation, triggered by systemic or local inflammatory effects of obesity itself, may account for the higher rates of airway disease in obese adolescents.

PMID:38039695 | DOI:10.1016/j.cyto.2023.156452

Ital J Pediatr. 2023 Dec 1;49(1):161. doi: 10.1186/s13052-023-01565-x.

ABSTRACT

BACKGROUND: The European Union (EU) approved the placement on European market of insect-based novel foods. Those foods were defined safe for the consumption for all European population, including children.

MAIN BODY: The nutrition committee of the Italian society of Paediatric Hepatology and Nutrition (SIGENP) performed literature research to understand benefits and risk of those use of those NF for Italian children. A special attention was reserved to the European Food Safety Agency (EFSA) reports upon which those novel insect-based were approved.

CONCLUSIONS: Based on the current knowledge, despite a possible ecological advantage, the group of expert suggests additional researches before pronouncing on a possible use for children diet, because of insufficient evidence on nutritional benefits and possible food allergies.

PMID:38041096 | DOI:10.1186/s13052-023-01565-x

Pediatr Pulmonol. 2023 Dec 1. doi: 10.1002/ppul.26775. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive disease. It affects multiple organ systems, including the liver, leading to CF-related liver disease (CFLD). It was noted that CFLD in Egyptian children with CF is more common than in non-Egyptian people with CF (pwCF). This study aimed to determine the incidence of CFLD and the potential risk factors for developing CFLD in Egyptian children. The correlation between CFLD and the various genotypes prevalent in Egyptian CF children will be discussed. In addition, comparison of CFLD in Egyptian and non-Egyptian CF patients will be presented.

METHODS: This cross-sectional study included 50 pwCF from Ain Sham University's Pediatric Pulmonology Clinic in Children's Hospital, Cairo, Egypt. The sweat chloride test and genetic studies were done at the time of diagnosis. Additionally, all subjects underwent detailed history taking, laboratory investigations, clinical assessment, and pelvic abdominal ultrasound for evaluation of hepatic involvement.

RESULTS: One-third of the Egyptian children with CF were found to have liver disease. The following independent risk factors for developing CFLD were identified as: male sex, severe genetic mutation (class I and II), long duration of CF disease, early onset of the CF, pancreatic insufficiency, as well as history of meconium ileus. In addition, diabetes mellitus and severe lung disease were proven to significantly increase the risk of developing CFLD.

CONCLUSION: CFLD is common in Egyptian pwCF. CFLD's risk factors are similar to other reported research from other countries in the region.

PMID:38038166 | DOI:10.1002/ppul.26775

Pediatr Pulmonol. 2023 Dec 1. doi: 10.1002/ppul.26786. Online ahead of print.

ABSTRACT

BACKGROUND: Rates of venous thromboembolism (VTE) are increasing in people with cystic fibrosis (PwCF). Providers treating VTE in PwCF have reported low confidence concerning anticoagulant drug selection, dose, duration, and drug-drug interactions. As there are currently no published reports regarding management of VTE in PwCF, our objective was to describe the management of VTE in PwCF.

METHODS: PwCF and VTE at the University of Utah Health were identified through electronic medical record searches. Patients were categorized into one of three treatment groups: warfarin, direct oral anticoagulant (DOAC), and low molecular weight heparin (LMWH). The primary outcome was episodes of major bleeding. Secondary outcomes included clinically relevant nonmajor (CRNM) bleeding.

RESULTS: Nine PwCF with a total of 12 unique VTE episodes were included in the study, with all but one episode associated with a peripherally inserted central catheter (PICC). Of the 12 VTE cases, 25% were treated with warfarin, 50% with a DOAC, and 25% with LMWH. There were no episodes of major bleeding and only one episode of CRNM bleeding (Hemoptysis) in the LMWH group. All anticoagulant doses and durations generally followed guidelines for persons without CF. DOACs were the most common VTE treatment, at doses and duration consistent with guidelines for persons without CF, with no major or CRNM bleeding.

CONCLUSION: VTE treatment in PwCF is generally consistent with guidelines for persons without CF with low rates of bleeding. DOACs are a potential option for treatment of VTE in PwCF, but more research is needed.

PMID:38038058 | DOI:10.1002/ppul.26786

J Cyst Fibros. 2023 Nov 30:S1569-1993(23)01721-6. doi: 10.1016/j.jcf.2023.11.015. Online ahead of print.

ABSTRACT

The concomitant use of elexacaftor/tezacaftor/ivacaftor (ETI) and strong CYP3A inducers including rifampin and rifabutin is not recommended due to the risk of drug-drug interactions (DDI). This presents a significant challenge to the treatment of non-tuberculous mycobacteria precluding the first line treatment. While rifabutin induces CYP3A activity, its effect appears to be moderate compared to rifampin. In this study, we investigated three cases in which concomitant use of rifabutin and CFTR modulators (ETI or ivacaftor monotherapy) was used, and these cases suggest that addition of rifabutin did not compromise the efficacy of ETI or ivacaftor as evidenced by pulmonary function and sweat chloride testing. A full physiologically based pharmacokinetic model predicted lung concentrations of ETI upon rifabutin coadministration to exceed the half-maximal effective concentrations (EC50) determined from chloride transport in phe508del human bronchial epithelial cells. This study provides preliminary evidence in support of the use of rifabutin in patients receiving ETI.

PMID:38036321 | DOI:10.1016/j.jcf.2023.11.015

Int J Infect Dis. 2023 Nov 28:S1201-9712(23)00774-9. doi: 10.1016/j.ijid.2023.11.013. Online ahead of print.

ABSTRACT

OBJECTIVES: The impressive improvements of CFTR function by elexacaftor/tezacaftor/ivacaftor (ETI) result in changes in the detection frequencies of Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA). We assessed determinants of the response to ETI with regards to SA and PA detection frequencies as documented in the German CF Registry for people with CF (pwCF) ≥12 years.

METHODS: We evaluated changes in the detection frequencies of SA and PA for 21 months before and after initiation of ETI and used different statistical tests to identify determinants of detection changes.

RESULTS: We included data from 1,092 pwCF with results from culture-dependent diagnostics for SA and PA detection from 7,944 microbiological samples prior and 6.845 microbiological samples after initiation of ETI. Detections of SA decreased from 54.3% to 44.3% and 40.2% and those of PA from 39.9% to 31.9% and 22.6% 3 and 21 months after initiation of therapy, respectively (all p<0.001). Reduction of SA and PA were observed in throat swabs and sputa, associated significantly with age, prior lung function and were dependent on pre-ETI colonization status.

CONCLUSIONS: The different patterns of reductions of SA and PA suggest that pathogen-specific biological processes govern the responsiveness of microbiological colonization towards ETI in pwCF.

PMID:38036261 | DOI:10.1016/j.ijid.2023.11.013