BMJ Open Respir Res. 2024 Aug 28;11(1):e002383. doi: 10.1136/bmjresp-2024-002383.

ABSTRACT

INTRODUCTION: People with cystic fibrosis (CF) are living longer and healthier lives with a growing number considering and pursuing parenthood. The decision of whether to become a parent is complex for people with CF, and CF is a major factor in reproductive decision-making. Unfortunately, in people with CF who become parents, there are no prospective studies of disease trajectory, no data on the impact of parenthood on mental health, disease self-management, or quality of life, and no research regarding non-genetic parenthood.

METHODS AND ANALYSIS: Health Outcomes of Parents with CF (HOPeCF) is a prospective, multicentre observational cohort study which will enrol 146 new parents with CF of children less than 5 years of age. The primary aim of this 60-month study is to assess the rate of lung function decline as impacted by mental health, parental stress and responsibility, and the use of CF transmembrane conductance regulator modulators. In addition, we will conduct dyadic interviews with a subset of study participants and their key supports (partner/family/friend) to inform future interventions.

ETHICS AND DISSEMINATION: This longitudinal, observational multicentre study is a necessary and timely step in understanding parental health outcomes in CF and will provide data essential for care guidance to people with CF, their partners, and healthcare providers. The University of Pittsburgh Institutional Review Board approved this study (STUDY23080161). As people with a variety of paediatric-onset chronic diseases are living longer and considering parenthood, these results may have widespread applicability and will be distributed at international meetings and submitted to peer-reviewed journals.

PMID:39209351 | DOI:10.1136/bmjresp-2024-002383

Lancet Respir Med. 2024 Aug 26:S2213-2600(24)00249-2. doi: 10.1016/S2213-2600(24)00249-2. Online ahead of print.

NO ABSTRACT

PMID:39208837 | DOI:10.1016/S2213-2600(24)00249-2

Lancet Respir Med. 2024 Aug 26:S2213-2600(24)00205-4. doi: 10.1016/S2213-2600(24)00205-4. Online ahead of print.

ABSTRACT

BACKGROUND: CFTR modulators are approved for approximately 90% of people with cystic fibrosis in the USA and provide substantial clinical benefit. N1303K (Asn1303Lys), one of the most common class 2 CFTR defects, has not been approved for these therapies by any regulatory agency. Preclinical investigation by our laboratories showed N1303K CFTR activation with elexacaftor-tezacaftor-ivacaftor (ETI). In this trial, we evaluate whether ETI improves CFTR function, measured by sweat chloride and other clinical outcomes, in people with cystic fibrosis and CFTRN1303K.

METHODS: In this prospective, open-label, single-arm trial, participants aged 12 years or older with cystic fibrosis encoding at least one N1303K variant and at least one CFTRN1303K allele who were ineligible for modulator therapy by US Food and Drug Administration labelling were given ETI for 28 days followed by a 28-day washout period at two cystic fibrosis centres in the USA. Participants received two orally administered pills of 100 mg elexacaftor, 50 mg tezacaftor, and 75 mg ivacaftor once daily in the morning, and 150 mg ivacaftor once daily in the evening. The primary endpoint was mean change in sweat chloride from baseline up to day 28 compared with mixed-effects models. Secondary endpoints were changes in percentage of predicted FEV1 (ppFEV1), Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain, BMI, and weight after ETI therapy. Safety was assessed in all participants who received at least one dose of the study drug and primary and secondary analyses were performed in all participants who took the study drug per protocol. The trial was registered at ClinicalTrials.gov (NCT03506061) and remains open for reporting purposes.

FINDINGS: Between June 7, 2022, and Oct 20, 2023, 20 participants (ten male and ten female) were enrolled and received ETI treatment. One participant was lost to follow-up but was included in intention-to-treat analyses. At 28 days, the mean sweat chloride reduction was -1·1 mmol/L (95% CI -5·3 to 3·1; p=0·61) with only one participant showing a sweat chloride decrease greater than 15 mmol/L. There was a mean increase in ppFEV1 from baseline at day 28 of 9·5 percentage points (6·7-12·3; p<0·0001) with 15 (75%) participants showing at least a 5% increase in ppFEV1. Improvements were also identified in mean CFQ-R respiratory domain score (20·8 increase [95% CI 11·9-29·8]; p<0·0001), BMI (0·4 kg/m2 increase [0·2-0·7]; p=0·0017), and weight (1·0 kg increase [0·4-1·7]; p=0·0020) after 28 days of ETI treatment. 14 (70%) of 20 participants had adverse events (12 [60%] mild, one [5%] moderate), with one (5%) serious adverse event of hospitalisation attributed to pneumonia. No deaths were recorded in the study.

INTERPRETATION: Individuals with CFTRN1303K showed no change in sweat chloride after 28 days of treatment with ETI. However, there were improvements in secondary clinical endpoints, which suggest clinical efficacy. Our approach provides support for the use of in vitro model systems to inform clinical trials for rare CFTR variants.

FUNDING: The Cystic Fibrosis Foundation and the US National Institutes of Health.

PMID:39208836 | DOI:10.1016/S2213-2600(24)00205-4

Oxf Open Immunol. 2024 Aug 22;5(1):iqae009. doi: 10.1093/oxfimm/iqae009. eCollection 2024.

ABSTRACT

The existence of commensal fungi that reside within the respiratory tract, termed the airway mycobiome, has only recently been discovered. Studies are beginning to characterize the spectrum of fungi that inhabit the human upper and lower respiratory tract but heterogeneous sampling and analysis techniques have limited the generalizability of findings to date. In this review, we discuss existing studies that have examined the respiratory mycobiota in healthy individuals and in those with inflammatory lung conditions such as asthma, chronic obstructive pulmonary disease and cystic fibrosis. Associations between specific fungi and features of disease pathogenesis are emerging but the precise functional consequences imparted by mycobiota upon the immune system remain poorly understood. It is imperative that further research is conducted in this important area as a more detailed understanding could facilitate the development of novel approaches to manipulating the mycobiome for therapeutic benefit.

PMID:39206335 | PMC:PMC11357796 | DOI:10.1093/oxfimm/iqae009

Viruses. 2024 Aug 16;16(8):1308. doi: 10.3390/v16081308.

ABSTRACT

The cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-dependent Cl- channel, is closely associated with multiple pathogen infections, such as SARS-CoV-2. However, whether the function of the CFTR is involved in herpes simplex virus (HSV) infection has not been reported. To evaluate the association of CFTR activity with HSV infection, the antiviral effect of CFTR inhibitors in epithelial cells and HSV-infected mice was tested in this study. The data showed that treatment with CFTR inhibitors in different concentrations, Glyh-101 (5-20 μM), CFTRi-172 (5-20 μM) and IOWH-032 (5-20 μM), or the gene silence of the CFTR could suppress herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2) replication in human HaCaT keratinocytes cells, and that a CFTR inhibitor, Glyh-101 (10-20 μM), protected mice from HSV-1 and HSV-2 infection. Intracellular Cl- concentration ([Cl-]i) was decreased after HSV infection via the activation of adenylyl cyclase (AC)-cAMP signaling pathways. CFTR inhibitors (20 μM) increased the reduced [Cl-]i caused by HSV infection in host epithelial cells. Additionally, CFTR inhibitors reduced the activity and phosphorylation of SGK1 in infected cells and tissues (from the eye and vagina). Our study found that CFTR inhibitors can effectively suppress HSV-1 and HSV-2 infection, revealing a previously unknown role of CFTR inhibitors in HSV infection and suggesting new perspectives on the mechanisms governing HSV infection in host epithelial cells, as well as leading to potential novel treatments.

PMID:39205282 | DOI:10.3390/v16081308

Pharmaceuticals (Basel). 2024 Aug 19;17(8):1085. doi: 10.3390/ph17081085.

ABSTRACT

Bacterial respiratory tract infections (e.g., in patients with cystic fibrosis) may be treated with the intravenous infusion of a piperacillin/tazobactam (P/T) solution through an elastomeric device. In the present work, we combined a 24-h drug stability study with an assessment of the drug solution flow rate during an in vitro simulated infusion. Experiments were performed in triplicate with two excipient-free generic P/T solutions and an excipient-containing proprietary P/T solution in saline (all 50/6.25 mg/mL) released from an elastomeric infusion device at 32 °C. The P/T solutions' stability was assessed by an HPLC-UV assay, pH and osmolality measurements, a visual assessment, and particle counting. Before these analyses, a forced degradation study was performed. To assess the flow rate, a precision scale was used to weigh the solution collected at the infusion line outlet. The stability criteria were <10% degradation and a flow rate within ± 15% of the nominal value over the 24-h infusion period: all three P/T solutions were found to be stable. The actual flow rate was lower than the expected flow rate; this difference was probably due to the drug solution's high viscosity and must be taken into account in clinical use.

PMID:39204190 | DOI:10.3390/ph17081085

Microorganisms. 2024 Jul 25;12(8):1522. doi: 10.3390/microorganisms12081522.

ABSTRACT

Biofilms, aggregates of bacteria enclosed in a self-produced matrix, have been implicated in various pediatric respiratory infections, including acute otitis media (AOM), otitis media with effusion (OME), adenoiditis, protracted bacterial bronchitis, and pulmonary exacerbations in cystic fibrosis. These infections are prevalent in children and often associated with biofilm-producing pathogens, leading to recurrent and chronic conditions. Biofilms reduce antibiotic efficacy, contributing to treatment failure and disease persistence. This narrative review discusses biofilm production by respiratory pathogens such as Streptococcus pneumoniae, non-typeable Haemophilus influenzae, Pseudomonas aeruginosa, and Staphylococcus aureus. It examines their mechanisms of biofilm formation, antibiotic resistance, and the challenges they present in clinical treatment. Various antibiofilm strategies have shown promise in vitro and in animal studies, including the use of N-acetylcysteine, enzymes like dispersin B, and agents disrupting quorum sensing and biofilm matrix components. However, their clinical application, particularly in children, remains limited. Traditional treatments for biofilm-associated diseases have not significantly evolved, even with biofilm detection. The transition from experimental findings to clinical practice is complex and requires robust clinical trials and standardized biofilm detection protocols. Addressing biofilms in pediatric respiratory infections is crucial for improving treatment outcomes and managing recurrent and chronic diseases effectively.

PMID:39203365 | DOI:10.3390/microorganisms12081522

Life (Basel). 2024 Aug 19;14(8):1026. doi: 10.3390/life14081026.

ABSTRACT

Obstructive sleep apnea (OSA) and cystic fibrosis (CF) are chronic conditions that profoundly impact quality of life. OSA, characterized by repeated episodes of upper airway collapse, can exacerbate CF symptoms due to nocturnal airway obstruction. Recent studies highlight the prevalence of OSA in CF patients, especially in adults, and its detrimental effects on health and quality of life. From April 2019 to December 2021, we conducted a study with 104 bronchiectasis patients at Marmara University Pendik Training and Research Hospital. After exclusions, 70 participants (35 CF and 35 non-CF) were included. Sleep parameters were assessed with polysomnography, and depressive mood was evaluated using the Zung Self-Rating Depression Scale (SDS). Daytime sleepiness was measured using the Epworth Sleepiness Scale (ESS). The statistical analyses included t-tests, chi-square tests, and logistic regression. Among the CF patients, depressive mood was significantly associated with female sex (OR: 4.28, 95% CI: 1.27-12.04) and anemia (OR: 7.87, 95% CI: 1.50-41.27). Higher ESS scores indicated greater daytime sleepiness in the depressive groups (p = 0.051). Depressive CF patients also had a significantly longer disease duration and more frequent annual exacerbations. No significant differences were found in total sleep time, sleep efficiency, or sleep stages between the depressive and non-depressive groups. A lower forced vital capacity (FVC) was observed in the depressive CF patients, although not significantly. Depression is prevalent among adult CF patients with OSA, with significant associations with female sex and anemia. These findings underscore the need for integrated care addressing both physical and mental health aspects, including interventions for respiratory symptoms, anemia management, and sleep quality enhancement to improve overall quality of life.

PMID:39202768 | DOI:10.3390/life14081026

Children (Basel). 2024 Jul 30;11(8):917. doi: 10.3390/children11080917.

ABSTRACT

Cystic fibrosis (CF) is a multisystem disorder characterized by progressive respiratory deterioration, significantly impacting both quality of life and survival. Over the years, lung ultrasound (LUS) has emerged as a promising tool in pediatric respiratory due to its safety profile and ease at the bedside. In the era of highly effective CF modulator therapies and improved life expectancy, the use of non-ionizing radiation techniques could become an integral part of CF management, particularly in the pediatric population. The present review explores the potential role of LUS in CF management based on available data, analyzing all publications from January 2015 to January 2024, focusing on two key areas: LUS in CF pulmonary exacerbation and its utility in routine clinical management. Nonetheless, LUS exhibits a robust correlation with computed tomography (CT) scans and serves as an additional, user-friendly imaging modality in CF management, demonstrating high specificity and sensitivity in identification, especially in consolidations and atelectasis in the CF population. Due to its ability, LUS could be an instrument to monitor exacerbations with consolidations and to establish therapy duration and monitor atelectasis over time or their evolution after therapeutic bronchoalveolar lavage. On the basis of our analysis, sufficient data emerged showing a good correlation between LUS score and respiratory function tests. Good sensitivity and specificity of the methodology have been found in rare CF pulmonary complications such as effusion and pneumothorax. Regarding its use in follow-up management, the literature reports a moderate correlation between LUS scores and the type, extent, and CT severity score of bronchiectasis. A future validation of ultrasound scores specifically in CF patients could improve the use of LUS to identify pulmonary exacerbations and monitor disease progression. However, further research is needed to comprehensively establish the role of LUS in the CF population, particularly in elucidating its broader utility and long-term impact on patient care.

PMID:39201852 | DOI:10.3390/children11080917

Antibiotics (Basel). 2024 Jul 26;13(8):701. doi: 10.3390/antibiotics13080701.

ABSTRACT

The number of antibiotic-resistant microbial infections is dramatically increasing, while the discovery of new antibiotics is significantly declining. Furthermore, the activity of antibiotics is negatively influenced by the ability of bacteria to form sessile communities, called biofilms, and by the microenvironment of the infection, characterized by an acidic pH, especially in the lungs of patients suffering from cystic fibrosis (CF). Antimicrobial peptides represent interesting alternatives to conventional antibiotics, and with expanding properties. Here, we explored the effects of an acidic pH on the antimicrobial and antibiofilm activities of the AMP Esc(1-21) and we found that it slightly lost activity (from 2- to 4-fold) against the planktonic form of a panel of Gram-negative bacteria, with respect to a ≥ 32-fold of traditional antibiotics. Furthermore, it retained its activity against the sessile form of these bacteria grown in media with a neutral pH, and showed similar or higher effectiveness against the biofilm form of bacteria grown in acidic media, simulating a CF-like acidic microenvironment, compared to physiological conditions.

PMID:39200001 | DOI:10.3390/antibiotics13080701

Bioengineering (Basel). 2024 Aug 13;11(8):826. doi: 10.3390/bioengineering11080826.

ABSTRACT

BACKGROUND: The upper respiratory mucosa plays a crucial role in both the physical integrity and immunological function of the respiratory tract. However, in certain situations such as infections, trauma, or surgery, it might sustain damage. Tissue engineering, a field of regenerative medicine, has found applications in various medical fields including but not limited to plastic surgery, ophthalmology, and urology. However, its application to the respiratory system remains somewhat difficult due to the complex morphology and histology of the upper respiratory tract. To date, a culture protocol for producing a handleable, well-differentiated nasal mucosa has yet to be developed. The objective of this review is to describe the current state of research pertaining to cell culture techniques used for producing autologous healthy human upper respiratory cells and mucosal tissues, as well as describe its clinical applications.

METHODS: A search of the relevant literature was carried out with no time restriction across Embase, Cochrane, PubMed, and Medline Ovid databases. Keywords related to "respiratory mucosa" and "culture techniques of the human airway" were the focus of the search strategy for this review. The risk of bias in retained studies was assessed using the Joanna Briggs Institute's (JBI) critical appraisal tools for qualitative research. A narrative synthesis of our results was then conducted.

RESULTS: A total of 33 studies were included in this review, and thirteen of these focused solely on developing a cell culture protocol without further use. The rest of the studies used their own developed protocol for various applications such as cystic fibrosis, pharmacological, and viral research. One study was able to develop a promising model for nasal mucosa that could be employed as a replacement in nasotracheal reconstructive surgery.

CONCLUSIONS: This systematic review extensively explored the current state of research regarding cell culture techniques for producing tissue-engineered nasal mucosa. Bioengineering the nasal mucosa holds great potential for clinical use. However, further research on mechanical properties is essential, as the comparison of engineered tissues is currently focused on morphology rather than comprehensive mechanical assessments.

PMID:39199784 | DOI:10.3390/bioengineering11080826

Biomolecules. 2024 Jul 25;14(8):904. doi: 10.3390/biom14080904.

ABSTRACT

Gene delivery therapy has emerged as a popular approach for the treatment of various diseases. However, it still poses the challenges of accumulation in target sites and reducing off-target effects. Aerosol gene delivery for the treatment of pulmonary diseases has the advantages of high lung accumulation, specific targeting and fewer systemic side effects. However, the key challenge is selecting the appropriate formulation for aerosol gene delivery that can overcome physiological barriers. There are numerous existing gene carriers under study, including viral vectors and non-viral vectors. With the development of biomaterials, more biocompatible substances have applied gene delivery via inhalation. Furthermore, many types of genes can be delivered through aerosol inhalation, such as DNA, mRNA, siRNA and CRISPR/Cas9. Aerosol delivery of different types of genes has proven to be efficient in the treatment of many diseases such as SARS-CoV-2, cystic fibrosis and lung cancer. In this paper, we provide a comprehensive review of the ongoing research on aerosol gene delivery therapy, including the basic respiratory system, different types of gene carriers, different types of carried genes and clinical applications.

PMID:39199292 | DOI:10.3390/biom14080904

BMC Cardiovasc Disord. 2024 Aug 28;24(1):457. doi: 10.1186/s12872-024-04129-x.

ABSTRACT

BACKGROUND: Although bronchiectasis has been shown to be associated with cardiovascular disease, there is limited evidence of an association with subclinical atherosclerosis, especially carotid intima-media thickness (CIMT).

METHODS: This prospective study compared CIMT among patients with and without bronchiectasis, and among bronchiectatic patients classified according to disease severity using the FACED score. The study was carried out at a major regional hospital and tertiary respiratory referral centre in Hong Kong.

RESULTS: Total 155 Chinese patients with non-cystic fibrosis (CF) bronchiectasis and 512 controls were recruited. The mean CIMT was 0.58 ± 0.10 mm, 0.63 ± 0.11 mm and 0.66 ± 0.08 mm respectively among controls, patients with mild-to-moderate bronchiectasis and patients with severe bronchiectasis. There was no statistically significant difference in CIMT between patients with mild-to-moderate bronchiectasis and controls. Multivariate linear regression revealed that CIMT was significantly increased in patients with severe bronchiectasis relative to controls. The same phenomenon was observed among patients without a history of cardiovascular disease or cardiovascular risk factors.

CONCLUSIONS: CIMT was significantly increased in patients with severe bronchiectasis compared with controls without bronchiectasis, but not among patients with mild-to-moderate bronchiectasis, which suggested the subclinical atherosclerosis to be more prevalent among patients with severe bronchiectasis.

PMID:39198746 | DOI:10.1186/s12872-024-04129-x

Korean J Physiol Pharmacol. 2024 Sep 1;28(5):435-447. doi: 10.4196/kjpp.2024.28.5.435.

ABSTRACT

Secretory proteins, including plasma membrane proteins, are generally known to be transported to the plasma membrane through the endoplasmic reticulum- to-Golgi pathway. However, recent studies have revealed that several plasma membrane proteins and cytosolic proteins lacking a signal peptide are released via an unconventional protein secretion (UcPS) route, bypassing the Golgi during their journey to the cell surface. For instance, transmembrane proteins such as the misfolded cystic fibrosis transmembrane conductance regulator (CFTR) protein and the Spike protein of coronaviruses have been observed to reach the cell surface through a UcPS pathway under cell stress conditions. Nevertheless, the precise mechanisms of the UcPS pathway, particularly the molecular machineries involving cytosolic motor proteins, remain largely unknown. In this study, we identified specific kinesins, namely KIF1A and KIF5A, along with cytoplasmic dynein, as critical players in the unconventional trafficking of CFTR and the SARS-CoV-2 Spike protein. Gene silencing results demonstrated that knockdown of KIF1A, KIF5A, and the KIF-associated adaptor protein SKIP, FYCO1 significantly reduced the UcPS of △F508-CFTR. Moreover, gene silencing of these motor proteins impeded the UcPS of the SARS-CoV-2 Spike protein. However, the same gene silencing did not affect the conventional Golgimediated cell surface trafficking of wild-type CFTR and Spike protein. These findings suggest that specific motor proteins, distinct from those involved in conventional trafficking, are implicated in the stress-induced UcPS of transmembrane proteins.

PMID:39198224 | DOI:10.4196/kjpp.2024.28.5.435

J Pediatr. 2024 Aug 27:114228. doi: 10.1016/j.jpeds.2024.114228. Online ahead of print.

NO ABSTRACT

PMID:39198099 | DOI:10.1016/j.jpeds.2024.114228

J Cyst Fibros. 2024 Aug 27:S1569-1993(24)00830-0. doi: 10.1016/j.jcf.2024.08.004. Online ahead of print.

ABSTRACT

Preventing transmissible infection is a priority in cystic fibrosis (CF) care. This is an update of a systematic review of the evidence for infection prevention and control interventions in CF. Our full protocol can be found on PROSPERO (CRD42018109999). We searched for studies and guidelines which included interventions for infection prevention and control in CF. We included 39 studies and 7 guidelines. Strategies included: cohort or individual segregation, hand hygiene, facemasks, equipment, enhanced adherence or a combination of these. Many studies showed a reduction in transmission with segregation. However, the certainty of evidence (using GRADE) was low or very low. Most guideline recommendations have little evidence to support them, with no updates since our original review. Undertaking RCTs in this area is ethically difficult. Large-scale registry-based studies may be the best pragmatic approach. Benefits of infection control must be balanced against the intrusion in the lives of people with CF.

PMID:39198075 | DOI:10.1016/j.jcf.2024.08.004

J Dent. 2024 Aug 26:105328. doi: 10.1016/j.jdent.2024.105328. Online ahead of print.

ABSTRACT

OBJECTIVES: Cystic Fibrosis is a multi-system disease, arising from a mutation of the cystic fibrosis transmembrane conductance regulator gene (CFTR). There is a lack of information regarding oral disease levels among people with cystic fibrosis. As part of an ongoing study assessing oral health in adults with cystic fibrosis at XXXXXXXXXX, a systematic review of available literature was conducted to ascertain the caries experience of people with cystic fibrosis. The objective was to systematically present and evaluate the literature comparing caries experience between people with cystic fibrosis and people without cystic fibrosis.

METHODS: Five online databases were searched; Embase, Scopus, Web of Science Core Collection, Medline Ebsco and Cochrane Library. Studies that reported caries experience in people with cystic fibrosis were included in this review.

RESULTS: The initial search identified 1199 publications from online databases. Twenty-one studies were included for qualitative analysis. Fourteen studies reported a lower caries experience in children with CF compared to children without CF, five studies reported a higher caries experience in adults with CF, and two studies found inconclusive evidence regarding the association between caries experience and CF status. All studies had a risk of bias that may influence results.

CONCLUSION: Despite a lack of complete unanimity between all studies, there is a general trend that children with cystic fibrosis have a lower caries experience than their healthy counterparts, whereas adults with cystic fibrosis have a higher caries experience. The review highlights the need for further studies involving adults with cystic fibrosis as the majority of studies primarily consist of paediatric populations.

CLINICAL SIGNIFICANCE: Dental practitioners should be aware that adults with cystic fibrosis have higher caries experience. Tailored approaches to dental care specific to cystic fibrosis individuals should be developed.

PMID:39197529 | DOI:10.1016/j.jdent.2024.105328

Am J Respir Crit Care Med. 2024 Aug 28. doi: 10.1164/rccm.202402-0458RL. Online ahead of print.

NO ABSTRACT

PMID:39197091 | DOI:10.1164/rccm.202402-0458RL

Eur J Clin Microbiol Infect Dis. 2024 Aug 28. doi: 10.1007/s10096-024-04921-9. Online ahead of print.

ABSTRACT

PURPOSE: Bacterial isolation is associated with worse outcomes after lung transplantation (LTx), and successful bacterial eradication is shown to improve long-term survival and pulmonary function. Outpatient Parenteral Antibiotic Therapy (OPAT) may be an effective therapeutic modality for bacterial eradication post-LTx.

METHODS: A single-center, retrospective analysis of OPAT characteristics, efficacy, safety, and costs in non-cystic fibrosis LTx recipients.

RESULTS: A total of 156 OPAT courses (from June 2019 to December 2022) were evaluated in 108 distinct LTx recipients. OPAT mainly consisted of dual antibiotic therapy (69%) for pulmonary bacterial isolation (97%), mostly Pseudomonas aeruginosa (66%). Successful eradication at 3 months post-OPAT was achieved in 71%. Eradication rate was significantly higher in patients treated after the first post-operative year (79%), compared to patients within the first year (61%) (p = 0.017). Eradication rate was similar for multidrug resistance (eradication rate 61%) versus no multidrug resistance (74%) (p = 0.116). Spirometry remained stable at 90 days post-OPAT. A statistically significant, but clinically negligible, increase in serum creatinine at 90 days post-OPAT was observed (1.33 mg/dL vs. 1.39 mg/dL, p < 0.001), yet unrelated to the antibiotic regimen used. OPAT-related hospital admissions occurred in 13% and line-related adverse events in 6%. Median number of hospitalization days saved per OPAT-course was 10 days (range 2-92), accounting for a total of 1841 avoided admission days and an estimated net cost reduction of 47% per treatment course.

CONCLUSION: OPAT is an effective and safe therapeutic modality for bacterial eradication post-LTx, associated with a significant reduction in hospitalization days and treatment costs.

PMID:39196488 | DOI:10.1007/s10096-024-04921-9

Anal Bioanal Chem. 2024 Aug 28. doi: 10.1007/s00216-024-05496-2. Online ahead of print.

ABSTRACT

The four cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators, ivacaftor, lumacaftor, tezacaftor, and elexacaftor, have revolutionised the treatment of CF by direct action on the protein target behind the disease's development. The aim was to develop and validate a quantification method for these CFTR modulators in plasma and breast milk to better understand inter-patient variability in pharmacokinetics and treatment outcome, including the risk of adverse drug reactions. The ability to monitor CFTR modulators in breast milk enables the estimation of the exposure of breastfed infant, with a potential concern for CFTR modulator-induced liver injury. The analysis was performed on a Thermo Vanquish Flex Binary UHPLC system coupled to a high-resolution mass spectrometer (HRMS), Thermo Q Exactive. The analytes were detected using positive electrospray ionisation in full scan mode. After sample preparation by protein precipitation, the supernatant was injected onto the LC system and the analytes were separated using a Zorbax SB-C18 Rapid Res HPLC column (3.5 µm, 4.6 × 75 mm). This is the first published method for CFTR modulators in breast milk. The validated quantification range for ivacaftor is 0.0050-10 µg/mL with a coefficient of variation < 6% and a mean accuracy of 97-106%; for lumacaftor, tezacaftor, and elexacaftor, the validated quantification range is 0.050-100 µg/mL with a coefficient of variation < 8% and a mean accuracy 93-106%. A simple and sensitive quantification method for CFTR modulators has been developed and used for routine analysis of human plasma and breast milk samples since 2022.

PMID:39196336 | DOI:10.1007/s00216-024-05496-2