Rev Med Liege. 2022 Sep;77(9):532-537.

ABSTRACT

Cystic fibrosis care is expensive. In Belgium, its financial support is not provided by powerful charities but by the national health system, which also sponsors the Belgian Cystic Fibrosis Registry. Recent data allow to better evaluate the quality of care for patients with cystic fibrosis in our country. Overall, it is high but varies from one centre to another. Similarly, use of the main symptomatic treatments is heterogeneous. Access to lung transplantation is one of the fluidest in the world. However, Belgium was one of the last medicalised countries to implement a neonatal screening programme for cystic fibrosis. It also lags behind in regard of the reimbursement of modulators of the CTFR gene function. This is especially detrimental for the lack of reimbursement of a recent highly effective combination of three modulators. The cost of this triple therapy is opaque and far too high. However, its effectiveness is impressive and, in the long term, around 90 % of Belgian patients with cystic fibrosis are expected to greatly benefit from it.

PMID:36082601

Front Cell Infect Microbiol. 2022 Aug 23;12:992214. doi: 10.3389/fcimb.2022.992214. eCollection 2022.

ABSTRACT

Chronic respiratory infections with the gram-negative bacterium Pseudomonas aeruginosa are an important co-morbidity for the quality of life and prognosis of people with cystic fibrosis (CF). Such long-term colonization, sometimes lasting up to several decades, represents a unique opportunity to investigate pathogen adaptation processes to the host. Our studies aimed to resolve if and to what extent the bacterial adaptation to the CF airways influences the fitness of the pathogen to grow and to persist in the lungs. Marker-free competitive fitness experiments of serial P. aeruginosa isolates differentiated by strain-specific SNPs, were performed with murine and human precision cut lung slices (PCLS). Serial P. aeruginosa isolates were selected from six mild and six severe CF patient courses, respectively. MPCLS or hPCLS were inoculated with a mixture of equal numbers of the serial isolates of one course. The temporal change of the composition of the bacterial community during competitive growth was quantified by multi-marker amplicon sequencing. Both ex vivo models displayed a strong separation of fitness traits between mild and severe courses. Whereas the earlier isolates dominated the competition in the severe courses, intermediate and late isolates commonly won the competition in the mild courses. The status of the CF lung disease rather than the bacterial genotype drives the adaptation of P. aeruginosa during chronic CF lung infection. This implies that the disease status of the lung habitat governed the adaptation of P. aeruginosa more strongly than the underlying bacterial clone-type and its genetic repertoire.

PMID:36081773 | PMC:PMC9446154 | DOI:10.3389/fcimb.2022.992214

Front Cell Infect Microbiol. 2022 Aug 23;12:969326. doi: 10.3389/fcimb.2022.969326. eCollection 2022.

ABSTRACT

Biofilms are multicellular microbial aggregates that can be associated with host mucosal epithelia in the airway, gut, and genitourinary tract. The host environment plays a critical role in the establishment of these microbial communities in both health and disease. These host mucosal microenvironments however are distinct histologically, functionally, and regarding nutrient availability. This review discusses the specific mucosal epithelial microenvironments lining the airway, focusing on: i) biofilms in the human respiratory tract and the unique airway microenvironments that make it exquisitely suited to defend against infection, and ii) how airway pathophysiology and dysfunctional barrier/clearance mechanisms due to genetic mutations, damage, and inflammation contribute to biofilm infections. The host cellular responses to infection that contribute to resolution or exacerbation, and insights about evaluating and therapeutically targeting airway-associated biofilm infections are briefly discussed. Since so many studies have focused on Pseudomonas aeruginosa in the context of cystic fibrosis (CF) or on Haemophilus influenzae in the context of upper and lower respiratory diseases, these bacteria are used as examples. However, there are notable differences in diseased airway microenvironments and the unique pathophysiology specific to the bacterial pathogens themselves.

PMID:36081767 | PMC:PMC9445362 | DOI:10.3389/fcimb.2022.969326

Polymers (Basel). 2022 Sep 2;14(17):3655. doi: 10.3390/polym14173655.

ABSTRACT

Pseudomonas aeruginosa contributes to many chronic infections and has been found to be resistant to multiple antibiotics. Pseudomonas use a quorum sensing system (QS) to control biofilm establishment and virulence factors, and, thus, quorum sensing inhibitors (QSIs), such as meta-bromo-thiolactone (mBTL), are promising anti-infective agents. Accordingly, this study intended to investigate the antibacterial and anti-virulence activity of mBTL-loaded calcium alginate nanoparticles (CANPs) against Pseudomonas aeruginosa and different QS mutants. The results show that the mBTL-CANPs had higher antibacterial activity, which was made evident by decreases in all tested strains except the ∆lasR/∆rhlR double mutant, with MIC50 (0.5 mg/mL) of mBTL-CANPs compared with free mBTL at MIC50 (˃1 mg/mL). The biofilm formation of P. aeruginosa and some QS-deficient mutants were reduced in response to 0.5-0.125 mg/mL of mBTL-encapsulating CANPs. The pyocyanin production of the tested strains except ∆lasA and ∆rhlR decreased when challenged with 0.5 mg/mL of mBTL-loaded NPs. The subsequent characterization of the cytotoxic effect of these NPs on human lung epithelial cells (A549) and cystic fibrosis fibroblast cells (LL 29) demonstrated that synthesized NPs were cytocompatible at MIC50 in both cell lines and markedly reduced the cytotoxic effect observed with mBTL alone on these cells. The resulting formulation reduced the P. aeruginosa strains' adhesion to A549 comparably with mBTL, suggesting their potential anti-adhesive effect. Given the virulence suppressing action, cytocompatibility, and enhanced anti-biofilm effect of mBTL-CANPs, and the advantage of alginate-based NPs as an antimicrobial delivery system these nanoparticles have great potential in the prophylaxis and treatment of infection caused by Pseudomonas aeruginosa.

PMID:36080730 | DOI:10.3390/polym14173655

Int J Environ Res Public Health. 2022 Sep 3;19(17):11039. doi: 10.3390/ijerph191711039.

ABSTRACT

BACKGROUND: Patients with chronic respiratory disease have low exercise capacity and limited physical activity (PA), which is associated with worsening dyspnoea, exacerbations, and quality of life. The literature regarding patients with non-cystic fibrosis bronchiectasis (non-CF BQ) is scarce, especially regarding the use of cardiopulmonary exercise tests (CPET) to assess the effects of home-based pulmonary rehabilitation programmes (HPRP). The aim was to evaluate the effect of an HPRP on the exercise capacity of non-CF BQ patients using CPET and PA using an accelerometer.

METHODS: Our study describes a non-pharmacological clinical trial in non-CF BQ patients at the Virgen Macarena University Hospital (Seville, Spain). The patients were randomised into two groups: a control group (CG), which received general advice on PA and educational measures, and the intervention group (IG), which received a specific 8-week HPRP with two hospital sessions. The variables included were those collected in the CPET, the accelerometer, and others such as a 6 min walking test (6MWT) and dyspnoea. The data were collected at baseline and at an 8-week follow-up.

RESULTS: After the intervention, there was a significant increase in peak VO2 in the IG, which was not evidenced in the GC (IG 66.8 ± 15.5 mL/min p = 0.001 vs. CG 62.2 ± 14.14 mL/min, p = 0.30). As well, dyspnoea according to the mMRC (modified Medical Research Council), improved significantly in IG (2.19 ± 0.57 to 1.72 ± 0.05, p = 0.047) vs. CG (2.07 ± 0.7 to 2.13 ± 0.64, p = 0.36). In addition, differences between the groups in walked distance (IG 451.19 ± 67.99 m, p = 0.001 vs. CG 433.13 ± 75.88 m, p = 0.981) and in physical activity (IG 6591 ± 3482 steps, p = 0.007 vs. CG 4824 ± 3113 steps, p = 0.943) were found.

CONCLUSION: Participation in a specific HPRP improves exercise capacity, dyspnoea, walked distance, and PA in non-CF BQ patients.

PMID:36078768 | DOI:10.3390/ijerph191711039

Int J Mol Sci. 2022 Sep 1;23(17):9993. doi: 10.3390/ijms23179993.

ABSTRACT

Mutations in the CFTR chloride channel result in intestinal obstructive episodes in cystic fibrosis (CF) patients and in CF animal models. In this study, we explored the possibility of reducing the frequency of obstructive episodes in cftr-/- mice through the oral application of a gut-selective NHE3 inhibitor tenapanor and searched for the underlying mechanisms involved. Sex- and age-matched cftr+/+ and cftr-/- mice were orally gavaged twice daily with 30 mg kg-1 tenapanor or vehicle for a period of 21 days. Body weight and stool water content was assessed daily and gastrointestinal transit time (GTT) once weekly. The mice were sacrificed when an intestinal obstruction was suspected or after 21 days, and stool and tissues were collected for further analysis. Twenty-one day tenapanor application resulted in a significant increase in stool water content and stool alkalinity and a significant decrease in GTT in cftr+/+ and cftr-/- mice. Tenapanor significantly reduced obstructive episodes to 8% compared to 46% in vehicle-treated cftr-/- mice and prevented mucosal inflammation. A decrease in cryptal hyperproliferation, mucus accumulation, and mucosal mast cell number was also observed in tenapanor- compared to vehicle-treated, unobstructed cftr-/- mice. Overall, oral tenapanor application prevented obstructive episodes in CFTR-deficient mice and was safe in cftr+/+ and cftr-/- mice. These results suggest that tenapanor may be a safe and affordable adjunctive therapy in cystic fibrosis patients to alleviate constipation and prevent recurrent DIOS.

PMID:36077390 | DOI:10.3390/ijms23179993

Int J Mol Sci. 2022 Aug 27;23(17):9724. doi: 10.3390/ijms23179724.

ABSTRACT

SARS-CoV-2 replicates in host cell cytoplasm. People with cystic fibrosis, considered at risk of developing severe symptoms of COVID-19, instead, tend to show mild symptoms. We, thus, analyzed at the ultrastructural level the morphological effects of SARS-CoV-2 infection on wild-type (WT) and F508del (ΔF) CFTR-expressing CFBE41o- cells at early and late time points post infection. We also investigated ACE2 expression through immune-electron microscopy. At early times of infection, WT cells exhibited double-membrane vesicles, representing typical replicative structures, with granular and vesicular content, while at late time points, they contained vesicles with viral particles. ∆F cells exhibited double-membrane vesicles with an irregular shape and degenerative changes and at late time of infection, showed vesicles containing viruses lacking a regular structure and a well-organized distribution. ACE2 was expressed at the plasma membrane and present in the cytoplasm only at early times in WT, while it persisted even at late times of infection in ΔF cells. The autophagosome content also differed between the cells: in WT cells, it comprised vesicles associated with virus-containing structures, while in ΔF cells, it comprised ingested material for lysosomal digestion. Our data suggest that CFTR-modified cells infected with SARS-CoV-2 have impaired organization of normo-conformed replicative structures.

PMID:36077122 | DOI:10.3390/ijms23179724

Int J Mol Sci. 2022 Aug 25;23(17):9612. doi: 10.3390/ijms23179612.

ABSTRACT

Cystic fibrosis (CF) is caused by mutations in the gene encoding of the cystic fibrosis transmembrane conductance regulator (CFTR), an anion-selective plasma membrane channel that mainly regulates chloride transport in a variety of epithelia. More than 2000 mutations, most of which presumed to be disease-relevant, have been identified in the CFTR gene. The single CFTR mutation F508del (deletion of phenylalanine in position 508) is present in about 90% of global CF patients in at least one allele. F508del is responsible for the defective folding and processing of CFTR, failing to traffic to the plasma membrane and undergoing premature degradation via the ubiquitin-proteasome system. CFTR is subjected to different post-translational modifications (PTMs), and the possibility to modulate these PTMs has been suggested as a potential therapeutic strategy for the functional recovery of the disease-associated mutants. Recently, the PTM mapping of CFTR has identified some lysine residues that may undergo methylation or ubiquitination, suggesting a competition between these two PTMs. Our work hypothesis moves from the idea that favors methylation over ubiquitination, e.g., inhibiting demethylation could be a successful strategy for preventing the premature degradation of unstable CFTR mutants. Here, by using a siRNA library against all the human demethylases, we identified the enzymes whose downregulation increases F508del-CFTR stability and channel function. Our results show that KDM2A and KDM3B downregulation increases the stability of F508del-CFTR and boosts the functional rescue of the channel induced by CFTR correctors.

PMID:36077010 | DOI:10.3390/ijms23179612

Int J Mol Sci. 2022 Aug 24;23(17):9597. doi: 10.3390/ijms23179597.

ABSTRACT

We compared the performance and levofloxacin (Quinsair) lung deposition of three nebulisers commonly used in CF (I-Neb Advance, eFlow rapid, and LC Plus) with the approved nebuliser Zirela. The delivered dose, delivery rate, and aerosol particle size distribution (APSD) for each device were determined using the methods described in the Pharmacopeia. High-resolution computed tomography scans obtained from seven adult patients with mild CF were used to generate computer-aided, three-dimensional models of their airway tree to assess lung deposition using functional respiratory imaging (FRI). The eFlow rapid and the LC Plus showed poor delivery efficiencies due to their high residual volumes. The I-Neb, which only delivers aerosols during the inspiratory phase, achieved the highest aerosol delivery efficiency. However, the I-Neb showed the largest particle size and lowest delivery rate (2.9 mg/min), which were respectively associated with a high extrathoracic deposition and extremely long nebulisation times (>20 min). Zirela showed the best performance considering delivery efficiency (159.6 mg out of a nominal dose of 240 mg), delivery rate (43.5 mg/min), and lung deposition (20% of the nominal dose), requiring less than 5 min to deliver a full dose of levofloxacin. The present study supports the use of drug-specific nebulisers and discourages the off-label use of general-purpose devices with the present levofloxacin formulation since subtherapeutic lung doses and long nebulisation times may compromise treatment efficacy and adherence.

PMID:36076992 | DOI:10.3390/ijms23179597

Diabet Med. 2022 Sep 8:e14958. doi: 10.1111/dme.14958. Online ahead of print.

ABSTRACT

AIM: To investigate whether the effect of cystic fibrosis-related diabetes (CFRD) on the composite outcome of mortality or transplant could act through lung function, pulmonary exacerbations and/or nutritional status.

METHODS: A retrospective cohort of adult cystic fibrosis (CF) patients who had not been diagnosed with CFRD were identified from the UK Cystic Fibrosis Registry (n=2,750). Rate of death or transplant was compared between patients who did and did not develop CFRD (with insulin use) during follow up using Poisson regression, separately by sex. Causal mediation methods were used to investigate whether lung function, pulmonary exacerbations and nutritional status lie on the causal pathway between insulin-treated CFRD and mortality/ transplant.

RESULTS: At all ages, the mortality/ transplant rate was higher in both men and women diagnosed with CFRD. Pulmonary exacerbations were the strongest mediator of the effect of CFRD on mortality/ transplant, with an estimated 15% [95% CI: 7%, 28%] of the effect at 2 years post-CFRD diagnosis attributed to exacerbations, growing to 24% [95% CI: 9%, 46%] at 4 years post-diagnosis. Neither lung function nor nutritional status were found to be significant mediators of this effect. Estimates were similar but with wider confidence intervals in a cohort that additionally included people with CFRD but not using insulin.

CONCLUSION: There is evidence that pulmonary exacerbations mediate the effect of CFRD on mortality but, as they are estimated to mediate less than one-quarter of the total effect, the mechanism through which CFRD influences survival may involve other factors.

PMID:36075586 | DOI:10.1111/dme.14958

Lancet Diabetes Endocrinol. 2022 Sep 2:S2213-8587(22)00256-X. doi: 10.1016/S2213-8587(22)00256-X. Online ahead of print.

NO ABSTRACT

PMID:36075247 | DOI:10.1016/S2213-8587(22)00256-X

Hum Gene Ther. 2022 Sep 8. doi: 10.1089/hum.2022.172. Online ahead of print.

ABSTRACT

The prospect of gene therapy for inherited and acquired respiratory disease has energized the research community since the 1980s, with cystic fibrosis, as a monogenic disorder, driving early efforts to develop effective strategies. The fact that there are still no approved gene therapy products for the lung, despite many early phase clinical trials, illustrates the scale of the challenge: in the 1990s, first generation non-viral and viral vector systems demonstrated proof-of-concept but low efficacy. Since then, there has been steady progress towards improved vectors with the capacity to overcome at least some of the formidable barriers presented by the lung. In addition, the inclusion of features such as codon optimisation and promoters providing long-term expression have improved the expression characteristics of therapeutic transgenes. Early approaches were based on gene addition, where a new DNA copy of a gene is introduced to complement a genetic mutation: however, the advent of RNA-based products that can directly express a therapeutic protein or manipulate gene expression, together with the expanding range of tools for gene editing, has stimulated the development of alternative approaches. This review discusses the range of vector systems being evaluated for lung delivery; the variety of cargoes they deliver, including DNA, antisense oligonucleotides, mRNA, siRNA and peptide nucleic acids; and exemplifies progress in selected respiratory disease indications.

PMID:36074947 | DOI:10.1089/hum.2022.172

Mol Biol Cell. 2022 Sep 8:mbcE22060233. doi: 10.1091/mbc.E22-06-0233. Online ahead of print.

ABSTRACT

RNF5 E3 ubiquitin ligase has multiple biological roles and has been linked to the development of severe diseases such as cystic fibrosis, acute myeloid leukemia, and certain viral infections, emphasizing the importance of discovering small molecule RNF5 modulators for research and drug development. The present study describes the synthesis of a new benzo[b]thiophene derivative, FX12 that acts as a selective small-molecule inhibitor and degrader of RNF5. We initially identified the previously reported STAT3 inhibitor, Stattic, as an inhibitor of dislocation of misfolded proteins from the endoplasmic reticulum (ER) lumen to the cytosol in ER-associated degradation. A concise structure-activity relationship campaign (SAR) around the Stattic chemotype led to the synthesis of FX12 that has diminished activity in inhibition of STAT3 activation and retains dislocation inhibitory activity. FX12 binds to RNF5 and inhibits its E3 activity in vitro as well as promotes proteasomal degradation of RNF5 in cells. RNF5 as a molecular target for FX12 was supported by the facts that FX12 requires RNF5 to inhibit dislocation and negatively regulates RNF5 function. Thus, this study developed a small molecule inhibitor and degrader of the RNF5 ubiquitin ligase, providing a chemical biology tool for RNF5 research and therapeutic development.

PMID:36074076 | DOI:10.1091/mbc.E22-06-0233

mBio. 2022 Sep 8:e0166322. doi: 10.1128/mbio.01663-22. Online ahead of print.

ABSTRACT

Traditional studies on the evolution of antibiotic resistance development use approaches that can range from laboratory-based experimental studies, to epidemiological surveillance, to sequencing of clinical isolates. However, evolutionary trajectories also depend on the environment in which selection takes place, compelling the need to more deeply investigate the impact of environmental complexities and their dynamics over time. Herein, we explored the within-patient adaptive long-term evolution of a Pseudomonas aeruginosa hypermutator lineage in the airways of a cystic fibrosis (CF) patient by performing a chronological tracking of mutations that occurred in different subpopulations; our results demonstrated parallel evolution events in the chromosomally encoded class C β-lactamase (blaPDC). These multiple mutations within blaPDC shaped diverse coexisting alleles, whose frequency dynamics responded to the changing antibiotic selective pressures for more than 26 years of chronic infection. Importantly, the combination of the cumulative mutations in blaPDC provided structural and functional protein changes that resulted in a continuous enhancement of its catalytic efficiency and high level of cephalosporin resistance. This evolution was linked to the persistent treatment with ceftazidime, which we demonstrated selected for variants with robust catalytic activity against this expanded-spectrum cephalosporin. A "gain of function" of collateral resistance toward ceftolozane, a more recently introduced cephalosporin that was not prescribed to this patient, was also observed, and the biochemical basis of this cross-resistance phenomenon was elucidated. This work unveils the evolutionary trajectories paved by bacteria toward a multidrug-resistant phenotype, driven by decades of antibiotic treatment in the natural CF environmental setting. IMPORTANCE Antibiotics are becoming increasingly ineffective to treat bacterial infections. It has been consequently predicted that infectious diseases will become the biggest challenge to human health in the near future. Pseudomonas aeruginosa is considered a paradigm in antimicrobial resistance as it exploits intrinsic and acquired resistance mechanisms to resist virtually all antibiotics known. AmpC β-lactamase is the main mechanism driving resistance in this notorious pathogen to β-lactams, one of the most widely used classes of antibiotics for cystic fibrosis infections. Here, we focus on the β-lactamase gene as a model resistance determinant and unveil the trajectory P. aeruginosa undertakes on the path toward a multidrug-resistant phenotype during the course of two and a half decades of chronic infection in the airways of a cystic fibrosis patient. Integrating genetic and biochemical studies in the natural environment where evolution occurs, we provide a unique perspective on this challenging landscape, addressing fundamental molecular mechanisms of resistance.

PMID:36073814 | DOI:10.1128/mbio.01663-22

Physiol Rep. 2022 Sep;10(17):e15340. doi: 10.14814/phy2.15340.

ABSTRACT

In cystic fibrosis (CF), the loss of cystic fibrosis transmembrane conductance regulator (CFTR) mediated Cl- and HCO3 - secretion across the epithelium acidifies the airway surface liquid (ASL). Acidic ASL alters two key host defense mechanisms: Rapid ASL bacterial killing and mucociliary transport (MCT). Aerosolized tromethamine (Tham) increases ASL pH and restores the ability of ASL to rapidly kill bacteria in CF pigs. In CF pigs, clearance of insufflated microdisks is interrupted due to abnormal mucus causing microdisks to abruptly recoil. Aerosolizing a reducing agent to break disulfide bonds that link mucins improves MCT. Here, we are interested in restoring MCT in CF by aerosolizing Tham, a buffer with a pH of 8.4. Because Tham is hypertonic to serum, we use an acidified formulation as a control. We measure MCT by tracking the caudal movement of individual tantalum microdisks with serial chest computed tomography scans. Alkaline Tham improves microdisk clearance to within the range of that seen in non-CF pigs. It also partially reverses MCT defects, including reduced microdisk recoil and elapse time until they start moving after methacholine stimulation in CF pig airways. The effect is not due to hypertonicity, as it is not seen with acidified Tham or hypertonic saline. This finding indicates acidic ASL impairs CF MCT and suggests that alkalinization of ASL pH with inhaled Tham may improve CF airway disease.

PMID:36073059 | DOI:10.14814/phy2.15340

Mol Med. 2022 Sep 7;28(1):108. doi: 10.1186/s10020-022-00535-z.

ABSTRACT

BACKGROUND: High-mobility group box 1 protein (HMGB1) is an ubiquitous nuclear protein that once released in the extracellular space acts as a Damage Associated Molecular Pattern and promotes inflammation. HMGB1 is significantly elevated during Pseudomonas aeruginosa infections and has a clinical relevance in respiratory diseases such as Cystic Fibrosis (CF). Salicylates are HMGB1 inhibitors. To address pharmacological inhibition of HMGB1 with small molecules, we explored the therapeutic potential of pamoic acid (PAM), a salicylate with limited ability to cross epithelial barriers.

METHODS: PAM binding to HMGB1 and CXCL12 was tested by Nuclear Magnetic Resonance Spectroscopy using chemical shift perturbation methods, and inhibition of HMGB1·CXCL12-dependent chemotaxis was investigated by cell migration experiments. Aerosol delivery of PAM, with single or repeated administrations, was tested in murine models of acute and chronic P. aeruginosa pulmonary infection in C57Bl/6NCrlBR mice. PAM efficacy was evaluated by read-outs including weight loss, bacterial load and inflammatory response in lung and bronco-alveolar lavage fluid.

RESULTS: Our data and three-dimensional models show that PAM is a direct ligand of both HMGB1 and CXCL12. We also showed that PAM is able to interfere with heterocomplex formation and the related chemotaxis in vitro. Importantly, PAM treatment by aerosol was effective in reducing acute and chronic airway murine inflammation and damage induced by P. aeruginosa. The results indicated that PAM reduces leukocyte recruitment in the airways, in particular neutrophils, suggesting an impaired in vivo chemotaxis. This was associated with decreased myeloperoxidase and neutrophil elastase levels. Modestly increased bacterial burdens were recorded with single administration of PAM in acute infection; however, repeated administration in chronic infection did not affect bacterial burdens, indicating that the interference of PAM with the immune system has a limited risk of pulmonary exacerbation.

CONCLUSIONS: This work established the efficacy of treating inflammation in chronic respiratory diseases, including bacterial infections, by topical delivery in the lung of PAM, an inhibitor of HMGB1.

PMID:36071400 | DOI:10.1186/s10020-022-00535-z

Ther Drug Monit. 2022 Aug 26. doi: 10.1097/FTD.0000000000001021. Online ahead of print.

ABSTRACT

BACKGROUND: Acute pulmonary exacerbations (APEs) in patients with adult cystic fibrosis (CF) are treated with a beta-lactam and an aminoglycoside for activity against Pseudomonas aeruginosa (PA). Emerging drug resistance and changing pharmacokinetic profile in an aging population involve a re-evaluation of tobramycin dosing recommendations. The objective of this study was to develop a population pharmacokinetic model and establish optimal dosing recommendations for tobramycin using Monte Carlo simulations.

METHODS: This retrospective clinical study and data collection were performed at the CF center of the McGill University Health Center (MUHC), Canada. Model development and simulations were performed using a nonlinear mixed-effect modeling approach (NONMEM, version 7.4.2). The ratios of maximal concentration (Cmax) to the minimal inhibitory concentration (MIC) (Cmax/MIC ≥ 8 and ≥ 10) and area under the curve (AUC) to the MIC (AUC/MIC ≥ 70 and ≥ 100) were evaluated.

RESULTS: Adult patients with CF (n = 51) treated with tobramycin were included in the study. Plasma concentrations of tobramycin were obtained for 699 samples from the MUHC database. The two-compartmental model best described the pharmacokinetics of tobramycin. The association of patient height with the central volume of distribution significantly improved this model. Height, rather than weight, induced the best reduction in objective function. According to simulations, doses between 3.4 mg/cm and 4.4 mg/cm were necessary to achieve Cmax/MIC values ≥ 8 and ≥ 10, respectively. However, higher doses were required to achieve the AUC/MIC targets.

CONCLUSION: This study demonstrated that height of the patients seems to be more suitable than their weight for dosing adjustments in adult patients with CF. According to this model, initial doses of tobramycin between 3.4 and 4.4 mg/cm should be recommended for patients with median height of 164 cm and weight of 55 kg to achieve the target plasma concentrations.

PMID:36070759 | DOI:10.1097/FTD.0000000000001021

J Pediatr Gastroenterol Nutr. 2022 Sep 6. doi: 10.1097/MPG.0000000000003605. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis-related liver disease (CFLD) begins early in life. Symptoms may be vague, mild or nonexistent. Progressive liver injury may be associated with decrements in patient health before liver disease is clinically apparent. We examined Health-Related Quality of Life (HRQOL) in children enrolled in a multi-center study of cystic fibrosis-related liver disease (CFLD) to determine the impact of early CFLD on general and disease-specific QOL.

METHODS: US patterns of normal (NL), heterogeneous (HTG), homogeneous (HMG), or nodular (NOD) were assigned in a prospective manner to predict those at risk for advanced CFLD. Parents were informed of results. We assessed parent/child-reported (age≥5 y) HRQOL by PedsQL 4.0 Generic Core and CF Questionnaire-revised (CFQ-R) prior to US and annually. HRQOL scores were compared by US pattern at baseline (prior to US), between baseline and 1-year and at 5 years. Multivariate analysis of variance (MANOVA) with Hotelling-Lawley trace tested for differences among US groups.

RESULTS: Prior to US, among 515 participants and their parents there was no evidence that HTG or NOD US was associated with reduced PedsQL/CFQ-R at baseline. Parents of NOD reported no change in PedsQL/CFQ-R over the next year. Child-report PedsQL/CFQ-R (95 NL, 20 NOD) showed improvement between baseline and year 5 for many scales, including Physical Function. Parents of HMG children reported improved CFQ-R scores related to weight.

CONCLUSIONS: Early undiagnosed or pre-symptomatic liver disease had no impact on generic or disease-specific HRQoL, and HRQoL was remarkably stable in children with CF regardless of liver involvement.An infographic is available for this article at: http://links.lww.com/MPG/C930.

PMID:36070552 | DOI:10.1097/MPG.0000000000003605

J Pediatr Gastroenterol Nutr. 2022 Sep 6. doi: 10.1097/MPG.0000000000003606. Online ahead of print.

ABSTRACT

People with cystic fibrosis (CF) and exocrine pancreatic insufficiency must take pancreatic enzyme replacement therapy (PERT) to prevent malnutrition and gastrointestinal (GI) symptoms. Finding better ways to manage GI complaints is a high priority for the CF community. We fielded a survey to assess the perspective of people affected by CF regarding symptoms attributed to and challenges associated with current PERT, to identify factors that affect participation in PERT studies and to understand attitudes towards an outcome measure that could be an alternative to the coefficient of fat absorption test. Persistent GI symptoms are commonly ascribed to PERT. Minimizing time commitment and maximizing patient safety were factors affecting participation in research. We demonstrate four generalizable ways to incorporate patient experience early in the research process to aid in development of new medications and help improve study enrollment.

PMID:36070542 | DOI:10.1097/MPG.0000000000003606

J Pediatric Infect Dis Soc. 2022 Sep 7;11(Supplement_2):S3-S12. doi: 10.1093/jpids/piac052.

ABSTRACT

Cystic fibrosis (CF) is one of the most common life-shortening genetic diseases in Caucasians. Due to abnormal accumulation of mucus, respiratory failure caused by chronic infections is the leading cause of mortality in this patient population. The microbiology of these respiratory infections includes a distinct set of opportunistic pathogens, including Pseudomonas aeruginosa, Burkholderia spp., Achromobacter spp., Stenotrophomonas maltophilia, anaerobes, nontuberculous mycobacteria, and fungi. In recent years, culture-independent methods have shown the polymicrobial nature of lung infections, and the dynamics of microbial communities. The unique environment of the CF airway predisposes to infections caused by opportunistic pathogens. In this review, we will highlight how the epidemiology and role in disease of these pathogens in CF differ from that in individuals with other medical conditions. Infectious diseases (ID) physicians should be aware of these differences and the specific characteristics of infections associated with CF.

PMID:36069904 | DOI:10.1093/jpids/piac052