Pharmaceutics. 2025 Mar 7;17(3):347. doi: 10.3390/pharmaceutics17030347.

ABSTRACT

Background:Pseudomonas aeruginosa (Pa) is the predominant pulmonary pathogen in persons with Cystic Fibrosis (CF). Nebulization with tobramycin or colistin is mostly applied but has a significant treatment burden. Dry powder (DP) inhalation may offer an attractive alternative. The aim of this study was to assess local tolerability and the systemic pharmacokinetic parameters of increasing doses of dry powder tobramycin. Methods: This was a local tolerability and pharmacokinetic evaluation pilot study DP tobramycin of three different doses inhaled through the Cyclops (30, 60, 120 mg) in ten persons with CF, aged 6-18 years, compared to nebulization of tobramycin solution. Results: Both nebulization of tobramycin in solution and inhalation of dry powder tobramycin were well tolerated. None of the participants showed a significant drop in FEV1 after inhalation. The only two adverse events were cough and bad taste in, respectively, 20% and 13% of all inhalations, compared to 10% cough and 60% bad taste with nebulization. Systemic tobramycin levels were not detected after 30 mg, detected only in 10% after 60 mg and in 30% after 120 mg, compared to 80% after nebulization. Conclusions: Inhalation of dry powder tobramycin using the Cyclops is well tolerated, with no significant drop in FEV1, and only mild adverse events of cough and bad taste. We found only a few detectable systemic tobramycin levels after inhalation of dry powder tobramycin. We recommend that future studies should focus on the relation between dose and inhaler resistance in different pediatric age groups.

PMID:40143011 | DOI:10.3390/pharmaceutics17030347

Pharmaceutics. 2025 Mar 1;17(3):318. doi: 10.3390/pharmaceutics17030318.

ABSTRACT

Background/Objectives: The increasing use of statins in people with cystic fibrosis (CF) necessitates the investigation of potential drug-drug interactions (DDI) of statins with cystic fibrosis transmembrane conductance regulator (CFTR) modulators, including elexacaftor, tezacaftor, and ivacaftor (ETI). The interactions may involve the potential inhibition of cytochrome P450 isoenzymes (CYPs), organic anion-transporting polypeptides (OATPs), and Breast Cancer Resistance Protein (BCRP) by ETI. This presents a therapeutic challenge in CF due to the potential for elevated statin levels, consequently heightening the risk of myopathy. This study aimed to predict potential DDIs between statins and ETI using a physiologically based pharmacokinetic (PBPK) modeling approach. Methods: We performed in vitro assays to measure the inhibitory potency of ETI against OATPs and CYP2C9 and incorporated these data into our PBPK models alongside published inhibitory parameters for BCRP and CYP3A4. Results: The PBPK simulation showed that atorvastatin had the highest predicted AUC ratio (3.27), followed by pravastatin (2.27), pitavastatin (2.24), and rosuvastatin (1.83). Conclusions: Based on these findings, rosuvastatin appears to exhibit a weak interaction with ETI, whereas other statins exhibited a moderate interaction, potentially requiring appropriate dose reductions. These data indicate potential clinically significant DDIs between ETI and certain statins, which warrants a clinical study to validate these findings.

PMID:40142982 | DOI:10.3390/pharmaceutics17030318

Microorganisms. 2025 Mar 18;13(3):681. doi: 10.3390/microorganisms13030681.

ABSTRACT

Cystic fibrosis (CF) patients experience higher risks of colorectal cancer but the pathogenesis is unclear. In the general population, polyketide synthase-positive (pks+) E. coli is implicated in intestinal carcinogenesis via the production of colibactin; however, the relevance in CF is unknown. In this study, we investigate pks+E. coli prevalence in CF and potential associations between pks+E. coli, gastrointestinal inflammation, and microbiome dynamics with fecal calprotectin and 16SrRNA gene taxonomic data. Cross-sectional analysis demonstrated no difference in pks+E. coli carriage between CF patients and healthy controls, 21/55 (38%) vs. 26/55 (47%), p = 0.32. Pks+E. coli was not associated with significant differences in mean (SD) calprotectin concentration (124 (154) vs. 158 (268) mg/kg; p = 0.60), microbial richness (159 (76.5) vs. 147 (70.4); p = 0.50) or Shannon diversity index (2.78 (0.77) vs. 2.65 (0.74); p = 0.50) in CF. Additionally, there was no association with exocrine pancreatic status (p = 0.2) or overall antibiotic use (p = 0.6). Longitudinally, CF subjects demonstrated intra-individual variation in pks+E. coli presence but no significant difference in overall prevalence. Future investigation into the effects of repeat exposure on risk profile and analysis of older CF cohorts is necessary to identify if associations with colorectal cancer exist.

PMID:40142573 | DOI:10.3390/microorganisms13030681

Microorganisms. 2025 Mar 4;13(3):592. doi: 10.3390/microorganisms13030592.

ABSTRACT

BACKGROUND: Inquilinus species are Gram-negative, non-sporulating, non-pigmented rods that are catalase-positive, indole-negative, and able to grow at various temperatures and in 1% NaCl. Infections due to Inquilinus spp. are increasingly identified, especially in patients with cystic fibrosis.

OBJECTIVE: This review aims to present all reported cases of Inquilinus spp. infections in humans, with an emphasis on data regarding epidemiology, antimicrobial resistance, antimicrobial treatment, and mortality.

METHODS: A narrative review based on a literature search of the PubMed/MedLine and Scopus databases was performed.

RESULTS: In total, 13 articles providing data on 25 patients with Inquilinus infections were included in the analysis. The median age was 19 years, while 60% were male. Cystic fibrosis was the predominant risk factor (92%). Respiratory tract infection was the most common type of infection (96%). Inquilinus limosus was the most commonly identified species. Polymicrobial infection was very common (77.3%). Microbial identification required the use of advanced molecular techniques, such as 16s rRNA sequencing. The pathogen exhibited resistance to beta-lactams, with the exception of carbapenems. The most commonly used antimicrobials included carbapenems (68.4%), followed by quinolones (57.9%) and aminoglycosides (52.6%). Mortality was low (4%).

CONCLUSIONS: Due to the potential of Inquilinus spp. to cause infection in patients with cystic fibrosis, and given the difficulties in microbial identification, clinicians and laboratory professionals should consider it in the differential diagnosis of patients with cystic fibrosis and respiratory tract infection not responding to beta-lactam treatment or with polymicrobial infections, especially when traditional techniques are used for microbial identification.

PMID:40142485 | DOI:10.3390/microorganisms13030592

Microorganisms. 2025 Feb 26;13(3):511. doi: 10.3390/microorganisms13030511.

ABSTRACT

Pseudomonas aeruginosa is associated with both community and hospital-acquired infections. It colonizes the lungs of cystic fibrosis (CF) patients, establishing an ecological niche where it adapts and evolves from early to chronic stages, resulting in deteriorating lung function and frequent exacerbations. With antibiotics resistance on the rise, there is a pressing need for alternative personalized treatments (such as bacteriophage therapy) to combat P. aeruginosa infections. In this study, we aimed to isolate and characterize phages targeting both early and chronic P. aeruginosa isolates and evaluate their potential for phage therapy. Four highly virulent phages belonging to myoviral, podviral, and siphoviral morphotypes were isolated from sewage samples. These phages have a broad host range and effectively target 62.5% of the P. aeruginosa isolates with a positive correlation to the early isolates. All the phages have a virulence index of ≥0.90 (0.90-0.98), and one has a large burst size of 331 PFU/cell and a latency period of 30 min. All phages are stable under a wide range of temperature and pH conditions. Genomic analysis suggests the four phages are strictly lytic and devoid of identifiable temperate phage repressors and genes associated with antibiotic resistance and virulence. More significantly, two of the phages significantly delayed the onset of larval death when evaluated in a lethal Galleria mellonella infection model, suggesting their promise as phage therapy candidates for P. aeruginosa infections.

PMID:40142404 | DOI:10.3390/microorganisms13030511

Medicina (Kaunas). 2025 Mar 12;61(3):489. doi: 10.3390/medicina61030489.

ABSTRACT

Background and Objectives: Cystic fibrosis (CF), caused by CFTR gene mutations, primarily affects the respiratory and gastrointestinal systems. Microbiota modulation through probiotics, prebiotics, or synbiotics may help restore microbial diversity and reduce inflammation. This study aimed to evaluate their efficacy in CF. Materials and Methods: A systematic review and meta-analysis of randomized controlled trials (RCTs) published between 2000 and 2024 was conducted in Cochrane, ScienceDirect, Web of Science, LILAC, BMC, PubMed, and SCOPUS following PRISMA guidelines. Methodological quality was assessed using the Jadad scale, and RevMan 5.4® estimated effects on pulmonary function (FEV1), exacerbations, hospitalizations, quality of life, and inflammatory markers. Results: Thirteen RCTs (n = 552), mostly in pediatric populations, were included. Most examined probiotics (e.g., Lactobacillus rhamnosus GG, L. reuteri), while four used synbiotics. Several studies reported reduced fecal calprotectin and proinflammatory interleukins (e.g., IL-6, IL-8), suggesting an anti-inflammatory effect. However, no significant differences were observed regarding hospitalizations or quality of life. Additionally, none of the studies documented serious adverse events associated with the intervention. The meta-analysis showed no significant decrease in exacerbations (RR = 0.81; 95% CI = 0.48-1.37; p = 0.43) or improvements in FEV1 (MD = 4.7; 95% CI = -5.4 to 14.8; p = 0.37), even in subgroup analyses. Sensitivity analyses did not modify the effect of the intervention on pulmonary function or exacerbation frequency, supporting the robustness of the findings. Conclusions: Current evidence suggests that probiotics or synbiotics yield inconsistent clinical benefits in CF, although some reduction in inflammatory markers may occur. Larger, multicenter RCTs with longer follow-up are needed for clearer conclusions. Until more definitive evidence is available, these supplements should be considered experimental adjuncts rather than standard interventions for CF management.

PMID:40142300 | DOI:10.3390/medicina61030489

Int J Mol Sci. 2025 Mar 14;26(6):2636. doi: 10.3390/ijms26062636.

ABSTRACT

Cystic Fibrosis (CF) is a life-shortening, multi-organ disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Prominent clinical features of CF take place in the lung, hallmarked by cycles of bacterial infection and a dysfunctional inflammatory airway response, leading to eventual respiratory failure. Bidirectional crosstalk between epithelial cells, leukocytes (e.g., neutrophils, macrophages) and bacteria via release of intra-cellular mediators is key to driving inflammation in CF airways. In recent years, a highly effective combination of therapeutics targeting the CFTR defect have revolutionized treatment in CF. Despite these advancements and due to the complexity of the immune response in the CF airway, the full impact of highly effective modulator therapy (HEMT) on airway inflammation is not fully determined. This review provides the evidence to date on crosstalk mechanisms between host epithelium, leukocytes and bacteria and examines the effect of HEMT on both soluble and membrane-derived immune mediators in clinical samples. The varied effects of HEMT on expression of key proteases, cytokines and extracellular vesicles (EVs) in relation to clinical parameters is assessed. Advances in treatment with HEMT have shown potential in dampening the chronic inflammatory response in CF airways. However, to fully quell inflammation and maximize lung tissue resilience, further interventions may be necessary. Exploring the effects of HEMT on key immune mediators paves the way for identifying new anti-inflammatory approaches targeting host immune cell interactions, such as EV-directed lung therapies.

PMID:40141278 | DOI:10.3390/ijms26062636

BMJ Open Respir Res. 2025 Mar 26;12(1):e003044. doi: 10.1136/bmjresp-2024-003044.

ABSTRACT

BACKGROUND: Respiratory virus infections are a major cause of morbidity in early life. During the SARS-CoV-2 pandemic, non-pharmaceutical interventions (NPIs) lead to worldwide changes in respiratory virus epidemiology. However, evidence regarding virus circulation in the outpatient setting remains largely unknown. The aim of this study is to longitudinally assess respiratory viruses in healthy infants before and during the SARS-CoV-2 pandemic in Switzerland.

METHODS: In this prospective observational birth cohort study, we followed 34 infants throughout the first year of life before and during the SARS-CoV-2 pandemic. We analysed 648 biweekly nasal swabs for nine different respiratory viruses by Multiplex-PCR and assessed respiratory symptoms, COVID-19 infections of family members and childcare status in weekly interviews. 712 nasal swabs from 32 infants analysed before the pandemic and published previously served as control group.

RESULTS: During the period with strict NPIs (pandemic I), most common respiratory viruses were not detected, with a rebound (driven by Adenovirus and Parainfluenza virus) after most NPIs were relaxed (pandemic II): prepandemic: 27%, pandemic I: 19%, pandemic II: 33%; historic: 36% of collected swabs per period, p<0.001. Human rhinovirus (HRV) prevalence persisted during NPIs presence, mainly in the form of asymptomatic HRV detection: prepandemic=24%, pandemic I=19%, pandemic II=25%, historic: 25%, p=0.3. SARS-CoV-2 detection (asymptomatic and symptomatic) was low, and only present after NPIs were relaxed: pandemic II=2.4%. No severe COVID-19 infections were reported.

DISCUSSION: In our cohort, infants did not contribute largely to spread of SARS-CoV-2. The role of persisting asymptomatic HRV prevalence is still unclear, but it might help to maintain population immunity to prevent more severe infections. Our results underscore the importance of capturing asymptomatic viruses via longitudinal community-based data assessment to better understand virus transmission.

PMID:40139841 | DOI:10.1136/bmjresp-2024-003044

Biochemistry. 2025 Mar 26. doi: 10.1021/acs.biochem.4c00780. Online ahead of print.

ABSTRACT

Lumacaftor and Ivacaftor are two FDA-approved medications currently used to treat cystic fibrosis (CF), a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride ion channel located in epithelial cell membranes; however, the detailed mechanism(s) of their action remains to be elucidated. Both drugs, termed modulators, bind CFTR at a protein-lipid interface, yet Lumacaftor acts at the endoplasmic reticulum (ER), while Ivacaftor acts at the plasma membrane (PM). A major difference among biological membranes is their level of cholesterol (viz., the ER, 5% cholesterol; the Golgi apparatus, 12.5%; and the PM, 30%). Therefore, we investigated the ability of each molecule to interact with membranes of the corresponding cholesterol content to determine if lipid cholesterol content provides a physical basis for their observed localized activity. Using differential scanning calorimetry and a terbium-based liposome disruption assay, we show that both Lumacaftor (a corrector) and Ivacaftor (a potentiator) penetrate/diffuse through membranes containing high cholesterol concentrations, such as in Golgi and the PM. The results further suggest that (1) Lumacaftor resides within membranes containing 5% cholesterol, supporting the proposition that Lumacaftor acts as a corrector of the CFTR channel at the ER level where the nascent protein is in its initial folding stage; and (2) Ivacaftor is well-suited to penetrate the PM and reach its binding pocket on CFTR. Our findings provide evidence that membrane cholesterol levels significantly modulate CFTR corrector/potentiator activity and consequently may affect sensitivity to clinical therapeutics in CF patients.

PMID:40138627 | DOI:10.1021/acs.biochem.4c00780

Pathogens. 2025 Mar 12;14(3):271. doi: 10.3390/pathogens14030271.

ABSTRACT

The Achromobacter genus comprises 22 species and various genogroups. Some species with higher virulence or antibiotic resistance are more likely to cause chronic infections in people with cystic fibrosis (CF). Current identification methods often fail to accurately distinguish between the species or result in misidentifications due to biochemical similarities. This study aims to develop an accurate qPCR protocol for species-level identification that is applicable in clinical diagnostic laboratories. Whole-genome sequencing of clinical isolates from different Achromobacter species identified species-specific single-nucleotide polymorphisms (SNPs) in two 16S gene regions. Based on these SNPs, two sets of primers and qPCR probes were designed to generate unique identification profiles. Thermal profiles were optimized, and qPCR was performed on serial bacterial DNA dilutions to determine the detection limit (LOD). Four probes successfully identified three species: A. xylosoxidans, A. dolens, and A. insuavis. Two additional probes were designed for novel genotypes unrelated to publicly available sequences. The LOD ranged from 0.005 pg/µL to 1 pg/µL. Combined probes achieved 100% sensitivity, with specificity ranging from 97.95% to 100%. This qPCR protocol enables accurate species identification, overcoming the limitations of current methods, and represents a reliable tool for clinical diagnostics.

PMID:40137756 | DOI:10.3390/pathogens14030271

Respirol Case Rep. 2025 Mar 24;13(3):e70146. doi: 10.1002/rcr2.70146. eCollection 2025 Mar.

ABSTRACT

Hepatotoxicity due to Elexacaftor/Tezacaftor/Ivacaftor (ETI) use has been well documented. There are no dose adjustments or increased-frequency monitoring algorithms recommended for people who experience elevated transaminases without cirrhosis, only suggested treatment interruption or withdrawal depending on the severity of the derangement. Here we describe a patient with non-cirrhotic hepatic steatosis who experienced persistently elevated liver function tests due to modulator therapy but demonstrated a remarkable response to a notably low dose of ETI.

PMID:40134928 | PMC:PMC11932953 | DOI:10.1002/rcr2.70146

J Fungi (Basel). 2025 Mar 9;11(3):210. doi: 10.3390/jof11030210.

ABSTRACT

Cystic fibrosis is a severe, inherited, life-limiting disorder, and over half of those living with CF are children. Persistent airway infection and inflammation, resulting in progressive lung function decline, is the hallmark of this disorder. Aspergillus colonization and infection is a well-known complication in people with CF and can evolve in a range of Aspergillus disease phenotypes, including Aspergillus bronchitis, fungal sensitization, and allergic bronchopulmonary aspergillosis (ABPA). Management strategies for children with CF are primarily aimed at preventing lung damage and lung function decline caused by bacterial infections. The role of Aspergillus infections is less understood, especially during childhood, and therefore evidence-based diagnostic and treatment guidelines are lacking. This narrative review summarizes our current understanding of the impact of Aspergillus on the airways of children and young people with CF.

PMID:40137248 | DOI:10.3390/jof11030210

Cells. 2025 Mar 19;14(6):459. doi: 10.3390/cells14060459.

ABSTRACT

Polycystic kidney disease (PKD) is the most common hereditary disorder that disrupts renal function and frequently progresses to end-stage renal disease. Recent advances have elucidated the critical role of primary cilia and ciliary ion channels, including transient receptor potential (TRP) channels, cystic fibrosis transmembrane conductance regulator (CFTR), and polycystin channels, in the pathogenesis of PKD. While some channels primarily function as chloride conductance channels (e.g., CFTR), others primarily regulate calcium (Ca+2) homeostasis. These ion channels are essential for cellular signaling and maintaining the normal kidney architecture. Dysregulation of these pathways due to genetic mutations in PKD1 and PKD2 leads to disrupted Ca+2 and cAMP signaling, aberrant fluid secretion, and uncontrolled cellular proliferation, resulting in tubular cystogenesis. Understanding the molecular mechanisms underlying these dysfunctions has opened the door for innovative therapeutic strategies, including TRPV4 activators, CFTR inhibitors, and calcimimetics, to mitigate cyst growth and preserve renal function. This review summarizes the current knowledge on the roles of ciliary ion channels in PKD pathophysiology, highlights therapeutic interventions targeting these channels, and identifies future research directions for improving patient outcomes.

PMID:40136708 | DOI:10.3390/cells14060459

Cells. 2025 Mar 9;14(6):400. doi: 10.3390/cells14060400.

ABSTRACT

Pulmonary homeostasis can be agitated either by external environmental insults or endogenous factors produced during respiratory/pulmonary diseases. The lungs counter these insults by initiating mechanisms of inflammation as a localized, non-specific first-line defense response. Cytokines are small signaling glycoprotein molecules that control the immune response. They are formed by numerous categories of cell types and induce the movement, growth, differentiation, and death of cells. During respiratory diseases, multiple proinflammatory cytokines play a crucial role in orchestrating chronic inflammation and structural changes in the respiratory tract by recruiting inflammatory cells and maintaining the release of growth factors to maintain inflammation. The issue aggravates when the inflammatory response is exaggerated and/or cytokine production becomes dysregulated. In such instances, unresolving and chronic inflammatory reactions and cytokine production accelerate airway remodeling and maladaptive outcomes. Pro-inflammatory cytokines generate these deleterious consequences through interactions with receptors, which in turn initiate a signal in the cell, triggering a response. The cytokine profile and inflammatory cascade seen in different pulmonary diseases vary and have become fundamental targets for advancement in new therapeutic strategies for lung diseases. There are considerable therapeutic approaches that target cytokine-mediated inflammation in pulmonary diseases; however, blocking specific cytokines may not contribute to clinical benefit. Alternatively, broad-spectrum anti-inflammatory approaches are more likely to be clinically effective. Herein, this comprehensive review of the literature identifies various cytokines (e.g., interleukins, chemokines, and growth factors) involved in pulmonary inflammation and the pathogenesis of respiratory diseases (e.g., asthma, chronic obstructive pulmonary, lung cancer, pneumonia, and pulmonary fibrosis) and investigates targeted therapeutic treatment approaches.

PMID:40136649 | DOI:10.3390/cells14060400

Rev Paul Pediatr. 2025 Mar 24;43:e2024155. doi: 10.1590/1984-0462/2025/43/2024155. eCollection 2025.

ABSTRACT

OBJECTIVE: Determine the immediate effect of forced expiration technique (FET) on the respiratory mechanics of children and adolescents with cystic fibrosis (CF). As a secondary objective, the effect of cough induced by FET was evaluated by comparing respiratory mechanics and lung function between those who coughed and those who did not during the FET.

METHODS: A before-after clinical trial was conducted with children and adolescents with CF aged six to 15 years. Respiratory mechanics parameters were assessed using the impulse oscillometry system (IOS) in three stages: basal IOS, post-huff IOS, and final post-diaphragmatic breathing exercises (DBE) IOS. For the intervention, FET was requested with five low-volume followed by three high-volume huffs, and finally ten DBE repetitions. Coughing occurred randomly and was not previously requested. To investigate whether FET-induced coughing alters oscillometric parameters, the participants were divided into two groups: those who presented with cough (CG) during the protocol and those who did not (NCG).

RESULTS: Forty-three children and adolescents with CF participated in the study (51.2% female), with an average age of 10.44±2.64 years, where forced expiratory value - FEV1=78.51±23.28%, and body mass index - BMI=17.18±2.24 kg/m2. The huffing sequence increased all oscillometric parameters, while DBE repetitions led to an increase in these parameters, without a complete return to baseline values. In terms of coughing, there was no significant difference between the NCG and CG in any of the parameters studied.

CONCLUSIONS: It was observed that, during the FET, diaphragmatic breathing exercises can attenuate the effort exerted by the forced expiratory maneuver on the airways.

PMID:40136119 | DOI:10.1590/1984-0462/2025/43/2024155

J Bacteriol. 2025 Mar 26:e0002925. doi: 10.1128/jb.00029-25. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic pathogen that uses several mechanisms to survive in the iron-limiting host environment. The innate immune protein calprotectin (CP) sequesters ferrous iron [Fe(II)], among other divalent transition metal ions, to limit its availability to pathogens. CP levels are increased in individuals with cystic fibrosis (CF), a hereditary disease that leads to chronic pulmonary infection by P. aeruginosa. We previously showed that aerobic CP treatment of P. aeruginosa induces a multi-metal starvation response that alters expression of several virulence properties. However, the CF lung is a hypoxic environment due to the growth of P. aeruginosa in dense biofilms. Here, we report that anaerobic CP treatment of P. aeruginosa induces many processes associated with an aerobic iron starvation response, including decreased phenazine production and increased expression of the PrrF small regulatory RNAs (sRNAs). However, the iron starvation response elicited by CP in anaerobic conditions shows characteristics that are distinct from responses observed in aerobic growth, including a lack of siderophore production and increased induction of genes for the FeoAB Fe(II) and Phu heme uptake systems. Also distinct from aerobic conditions, CP treatment induces expression of genes for predicted manganese transporters MntH1 and MntH2 during anaerobic growth while eliciting a less robust zinc starvation response compared to aerobic conditions. Induction of mntH2 is dependent on the PrrF sRNAs, suggesting a novel example of metal regulatory cross-talk. Thus, anaerobic CP treatment results in a multi-metal starvation response with key distinctions from aerobic conditions, revealing differences in P. aeruginosa metal homeostasis during anaerobic growth.IMPORTANCEIron is critical for most microbial pathogens, and the innate immune system sequesters this metal to limit microbial growth. Pathogens must overcome iron sequestration to survive during infection. For many pathogens, iron homeostasis has primarily been studied in aerobic conditions. Nevertheless, some host environments are hypoxic, including chronic lung infection sites in individuals with cystic fibrosis (CF). Here, we use the innate immune protein calprotectin, which sequesters divalent metal ions including Fe(II), to study the anaerobic iron starvation response of a common CF lung pathogen, Pseudomonas aeruginosa. We report several distinctions of this response during anaerobiosis, highlighting the importance of carefully considering the host environment when investigating the role of nutritional immunity in host-pathogen interactions.

PMID:40135923 | DOI:10.1128/jb.00029-25

J Bacteriol. 2025 Mar 26:e0011623. doi: 10.1128/jb.00116-23. Online ahead of print.

ABSTRACT

Staphylococcus aureus asymptomatically colonizes the nasal cavity and pharynx of up to 60% of the human population and, as an opportunistic pathogen, can breach its normal habitat, resulting in life-threatening infections. S. aureus infections are of additional concern for populations with impaired immune function such as those with cystic fibrosis (CF) or chronic granulomatous disease. Multi-drug resistance is increasingly common in S. aureus infections, creating an urgent need for new antimicrobials or compounds that improve efficacy of currently available antibiotics. S. aureus biofilms, such as those found in the lungs of people with CF and in soft tissue infections, are notoriously recalcitrant to antimicrobial treatment due to the characteristic metabolic differences associated with a sessile mode of growth. In this work, we show that another CF pathogen, Burkholderia cenocepacia, produces one or more secreted compounds that can prevent S. aureus biofilm formation and inhibit existing S. aureus biofilms. The B. cenocepacia-mediated antagonistic activity is restricted to S. aureus species and perhaps some other staphylococci; however, this inhibition does not necessarily extend to other Gram-positive species. This inhibitory activity is due to death of S. aureus through a contact-independent mechanism, potentially mediated through the siderophore pyochelin and perhaps additional compounds. This works paves the way to better understanding of interactions between these two bacterial pathogens.IMPORTANCEStaphylococcus aureus is a major nosocomial pathogen responsible for infecting thousands of people each year. Some strains are becoming increasingly resistant to antimicrobials, and consequently new treatments must be sought. This paper describes the characterization of one or more compounds capable of inhibiting S. aureus biofilm formation and may potentially lead to development of a new therapeutic.

PMID:40135855 | DOI:10.1128/jb.00116-23

J Cyst Fibros. 2025 Mar 24:S1569-1993(25)00077-3. doi: 10.1016/j.jcf.2025.03.009. Online ahead of print.

ABSTRACT

BACKGROUND: We aimed to build a cohort of Maternal-Cystic Fibrosis (CF) fetal dyads treated in utero with Variant Specific Therapy (VST), to assess the efficacy on Meconium Ileus (MI) and potential adverse effects of treatment.

METHODS: Dyads were included if the foetus had a genetic diagnosis of CF and carried at least one variant responsive to VST. Standardized assessment included pre-VST Magnetic Resonance Imaging (MRI), repeated ultrasound (US), and VST drug concentrations in cord blood, maternal and infant plasma.

RESULTS: We enrolled 13 dyads. One withdrew from the study. VST therapies (Elexacaftor (ELX)/Tezacaftor (TEZ)/Ivacaftor(IVA) (ETI) n = 11, ivacaftor (IVA) n = 1) were administered to the pregnant women between 19 and 36 weeks' of gestation for a median[IQR] of 35[55] days, either as a curative indication of MI (n = 8) or as a tertiary prevention of fetal CF-related intestinal symptoms (n = 4). One foetus experienced increased bowel dilatation after ETI introduction. MRI revealed intestinal atresia. One dyad received only 2 doses. In the other 6 cases, resolution of MI was observed within 14[10] days of ETI. Fetal development and neonatal tolerance were excellent. Fecal elastase at birth was always below 200 ng/g even in the ETI breast-fed infant. Cord-to-maternal concentration yielded median ratios of 0.40 for ELX, 0.54 for IVA and 1.59 for TEZ.

CONCLUSION: ETI administration from the third trimester of pregnancy enables MI resolution. Trans-placental transfer is high. Fetal tolerance at ETI initiation needs to be monitored by a standardized assessment.

PMID:40133101 | DOI:10.1016/j.jcf.2025.03.009

BMJ Open. 2025 Mar 25;15(3):e091357. doi: 10.1136/bmjopen-2024-091357.

ABSTRACT

INTRODUCTION: Target trial emulation is a framework for evaluating the effects of treatments using observational data. The trial emulation approach involves specifying key elements of a protocol for a target trial (a randomised controlled trial designed to address the question of interest) and then describing how best to emulate the trial using observational data. Recent years have seen an uptake of target trial emulation in several disease areas, although there are limited examples in cystic fibrosis (CF). This protocol describes a study which aims to assess the applicability of target trial emulation in CF. We aim to emulate an existing trial in CF and assess to what extent the results from the trial can be replicated using registry data.

METHODS AND ANALYSIS: The target trial is a published randomised controlled trial which found evidence for beneficial effects of azithromycin use on lung function in young adults with CF. Two emulated trials are planned: one using data from the UK CF Registry and one using data from the US CF Registry. The inclusion and exclusion criteria, treatment and outcome definitions, follow-up period, and estimand of interest are all designed to match the published trial as closely as possible. The analysis step of the trial emulations will use causal inference methods to control for confounding. Results obtained in the emulated trials using registry data will be compared with those from the target trial.

ETHICS AND DISSEMINATION: Ethical approval has been granted by the London School of Hygiene and Tropical Medicine Ethics Committee (Ref: 29609). This study has also been approved by the UK CF Registry Research Committee and the North Star Review Board. The results of this study will be published in a peer-reviewed journal and presented at relevant scientific conferences.

PMID:40132841 | DOI:10.1136/bmjopen-2024-091357

Respir Med. 2025 Mar 23:108052. doi: 10.1016/j.rmed.2025.108052. Online ahead of print.

ABSTRACT

PURPOSE: Nontuberculous mycobacterial pulmonary disease (NTMPD) is a chronic, often progressive condition associated with a significant symptom burden and increased mortality. Goals of NTMPD treatment include microbiological eradication, symptom reduction, improved quality of life (QoL), and preventing disease progression. Antibiotics are used to reduce microbial burden and cultures of sputum are used to guide treatment. However, it is unclear whether achieving culture-negative status (often called "culture conversion") is associated with improved clinical outcomes. Studies use a variety of measures including symptom burden, radiological status, lung function, six-minute walk test distance, QoL assessments, and mortality to evaluate clinical outcomes related to changes in how patients feel, function, and survive. There is strong interest in more clearly understanding which clinical benefits may be associated with culture conversion. As NTMPD can cause sustained structural lung damage and declines in long-term pulmonary function, it is important to have clear evidence if prevention of these morbidities is associated with culture conversion.

METHODS: This targeted literature review summarizes the published evidence regarding associations between sputum culture conversion and clinical outcomes in patients with NTMPD. Identified studies used varying definitions of culture conversion and treatment success, making interpretation of outcomes across studies challenging.

RESULTS: Although some studies suggest an association between culture conversion and aspects of clinical improvement, overall, there are currently few high-quality studies supporting a link.

CONCLUSION: Further clarification of the relationship between culture conversion and clinical outcomes would be helpful in improving clinical monitoring and therapeutic decision-making during the treatment of patients with NTMPD.

PMID:40132751 | DOI:10.1016/j.rmed.2025.108052