Treatment Of Cystic Fibrosis Patients Research Articles

The microenvironment in antibiotic susceptibility testing.

Antibiotic susceptibility testing (AST) by agar diffusion has been repeatedly standardized and, in most cases, gives results which predict clinical success when antibiotic treatment is based on such results. The formation of the inhibition zone is due to a transition from planktonic to biofilm mode of growth. The kinetics of the interaction of antibiotics with bacteria is similar during AST by agar diffusion and during administration of antibiotics to the patients. However, the Mueller-Hinton agar (MHA) recommended for AST agar diffusion test is fundamentally different from the composition of the interstitial fluid in the human body where the infections take place and human cells do not thrive in MH media. Use of RPMI 1640 medium designed for growth of eucaryotic cells for AST of Pseudomonas aeruginosa against azithromycin results in lower minimal inhibitory concentration, compared to results obtained by MHA. The reason is that the RPMI 1640 medium increases uptake and reduces efflux of azithromycin compared to MHA. During treatment of cystic fibrosis patients with azithromycin, mutational resistance occur which is not detected by AST with MHA. Whether this is the case with other antibiotics and bacteria is not known but it is of clinical importance to be studied.

HPLC method for simultaneous quantification of lumacaftor and ivacaftor bulk and pharmaceutical formulations

In 2015, the Food and Drug Administration granted approval for the use of lumacaftor 200 mg and ivacaftor 125 mg in the treatment of cystic fibrosis patients who possess the F508del mutation, namely those who are 12 years of age or older. Since its approval, the medicine has been implemented in clinical settings, although the presence of numerous disputes, with the aim of mitigating disease symptoms and enhancing the overall quality of life. Given the existing gaps in the literature regarding the analysis of the amalgamation of these two active substances, a straightforward and practical HPLC approach has been devised in adherence to the guidelines outlined in the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q2(R1) document. To accomplish this objective, the process of separation was successfully carried out using a monolithic silica stationary phase (Chromolith High Resolution RP-18e, 100 mm × 4.6 mm i.d., Merck KGaA, Darmstadt, Germany). The separation process was conducted using a gradient mode. The initial composition of the mobile phase consisted of acetonitrile and a phosphate buffer solution with a concentration of 0.030 M and a pH of 3.5. The flow rate was recorded as 1.0 mL/min, and avanafil was used as an internal standard. The improved and verified approach has demonstrated successful application in bulk and pharmaceutical formulation evaluations when utilizing the ivacaftor/lumacaftor combination.

Antibiotic prescription patterns in Spanish cystic fibrosis patients: results from a national multicenter study

ObjectiveInformation about antibiotic prescription patterns for cystic fibrosis (CF) patients and, specifically, about inhaled treatment strategies for their management is lacking in Spain due to the absence of a national patient registry. In this study we present data about antibiotic prescription in the Spanish CF context that were obtained in a multicenter study, being inhaled treatment strategies the special focus of this work. MethodsTwenty-four specialized CF units (12 adult, 12 pediatric) from 17 tertiary-care hospitals covering all Spanish Autonomous Communities provided sputa and clinical data from 15 consecutive patients. Data about antibiotic and non-antibiotic therapies prescribed to these patients during the year prior inclusion (2013) were retrospectively collected. ResultsThe multicenter study included 341 CF patients from all age groups and clinical status. The prevalence of oral, inhaled and intravenous therapies was 89% (n = 302), 80% (n = 273) and 31% (n = 105), respectively. The most prevalent oral agents were ciprofloxacin (n = 177, 59%), cotrimoxazole (n = 109, 36%) and amoxicillin-clavulanate (n = 99, 33%), whereas ceftazidime (n = 53, 50%), tobramycin (n = 43, 41%) and meropenem (n = 41, 49%) were the most prevalent intravenous ones. Two or more different inhaled antibiotics were administered to 67 patients (24%), 51 of them receiving 2 drugs continuously in alternating schemes. Nebulization of intravenous specific antibiotics was common (n = 39) and, in some cases, was used for maintenance purposes. ConclusionsThese results show that the treatment of CF patients is evolving more rapidly than clinical consensus guidelines. Clinical trials evaluating new specific inhaled combinations and new alternative treatment regimes of the existing ones are needed.

Experimental evolution of Pseudomonas aeruginosa to colistin in spatially confined microdroplets identifies evolutionary trajectories consistent with adaptation in microaerobic lung environments.

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

The safety and toxicity profile of SPL84, an inhaled antisense oligonucleotide for treatment of cystic fibrosis patients with the 3849 +10kb C->T mutation, supports a Phase 1/2 clinical study

ABSTRACT Introduction SPL84 is an inhaled antisense oligonucleotide (ASO) in development for the treatment of cystic fibrosis (CF) patients carrying the 3849 + 10kb C->T (3849) mutation. To support the initiation of the first clinical study, a full battery of safety and toxicology studies were performed. Research design and methods SPL84 was administered by inhalation to mice and monkeys to determine the no observed adverse effect level (NOAEL) and establish sufficient safety margins for the starting clinical dose. Results There were no preclinical safety findings with SPL84; no related clinical signs, nor any effect on body weight, food consumption, or clinical pathology. The microscopic changes in the lungs were regarded as non-adverse and reflected a normal clearance process for inhaled compounds. Systemic exposure in both species was low. The NOAEL for mice and monkeys was the highest administered dose in both species, resulting in safety margins ~ 40X the proposed starting clinical dose. Conclusion These successful results supported the initiation of a phase 1/2 clinical study of SPL84 (ongoing), assessing the safety, tolerability, and pharmacokinetics of a single ascending dose in healthy subjects to be followed by assessment of safety, tolerability, pharmacokinetics, and preliminary efficacy of multiple ascending doses in CF patients carrying the 3849 mutation.

Chinese experts consensus statement: diagnosis and treatment of cystic fibrosis (2023)

Chinese experts consensus statement: diagnosis and treatment of cystic fibrosis (2023)

Antimicrobial sensitivity pattern of children with cystic fibrosis in Bangladesh: a lesson from a specialized Sishu (Children) Hospital

BackgroundInfection control in cystic fibrosis (CF) patients plays a crucial role in improving the survival of patients with CF. Antimicrobial sensitivity patterns in these patient groups in our country are currently lacking. Therefore, the purpose of the study was to evaluate the microbiological cultures and antimicrobial susceptibility pattern of pediatric CF patients.MethodA total of 50 respiratory samples were prospectively collected from the period between February 2021 and October 2021. Sputum and oropharyngeal swabs were processed for culture and microbiological testing. Sample collection and evaluation were performed according to the Good Laboratory Practice guidelines (GLP). Informed written consent was ensured before participation. Statistical analysis was performed with SPSS v 26.ResultThe median age of the children was 30 months (6–120) months, with a male predominance (66% vs 34%). Single and two organisms were isolated in 72% (n = 36) and 12% (n = 6) of cases, respectively. During the study period, 36% of the patients harbored Pseudomonas aeruginosa, 18% harbored Klebsiella pneumoniae, and both Staphylococcus aureus and Escherichia coli were detected in 16% of cases. Levofloxacin was found to be the most active antibiotic agent with 100% susceptibility. In contrast, nearly all isolates were resistant to amoxicillin, erythromycin and rifampicin.ConclusionLevofloxacin is the most effective agent to treat CF patients. Active surveillance of the resistance pattern should always continue to be promoted.

Colistin-degrading proteases confer collective resistance to microbial communities during polymicrobial infections

BackgroundThe increasing prevalence of resistance against the last-resort antibiotic colistin is a significant threat to global public health. Here, we discovered a novel colistin resistance mechanism via enzymatic inactivation of the drug and proposed its clinical importance in microbial communities during polymicrobial infections.ResultsA bacterial strain of the Gram-negative opportunistic pathogen Stenotrophomonas maltophilia capable of degrading colistin and exhibiting a high-level colistin resistance was isolated from the soil environment. A colistin-degrading protease (Cdp) was identified in this strain, and its contribution to colistin resistance was demonstrated by growth inhibition experiments using knock-out (Δcdp) and complemented (Δcdp::cdp) mutants. Coculture and coinfection experiments revealed that S. maltophilia carrying the cdp gene could inactivate colistin and protect otherwise susceptible Pseudomonas aeruginosa, which may seriously affect the clinical efficacy of the drug for the treatment of cystic fibrosis patients with polymicrobial infection.ConclusionsOur results suggest that Cdp should be recognized as a colistin resistance determinant that confers collective resistance at the microbial community level. Our study will provide vital information for successful clinical outcomes during the treatment of complex polymicrobial infections, particularly including S. maltophilia and other colistin-susceptible Gram-negative pathogens such as P. aeruginosa.F8-_RZYnrmbideKrzEmgifVideo abstract

Impact of CFTR Modulators on Beta-Cell Function in Children and Young Adults with Cystic Fibrosis.

Background: To date, no consistent data are available on the possible impact of CFTR modulators on glucose metabolism. The aim of this study was to test the hypothesis that treatment with CFTR modulators is associated with an improvement in the key direct determinants of glucose regulation in children and young adults affected by Cystic Fibrosis (CF). Methods: In this study, 21 CF patients aged 10–25 underwent oral glucose tolerance test (OGTT) before and after 12–18 months of treatment with Lumacaftor/Ivacaftor or Elexacaftor-Ivacaftor-Tezacaftor. β-cell function (i.e., first and second phase of insulin secretion measured as derivative and proportional control, respectively) and insulin clearance were estimated by OGTT mathematical modelling. Insulin sensitivity was estimated by the Oral Glucose Sensitivity Index (OGIS). The dynamic interplay between β-cell function, insulin clearance and insulin sensitivity was analysed by vector plots of glucose-stimulated insulin bioavailability vs. insulin sensitivity. Results: No changes in glucose tolerance occurred after either treatment, whereas a significant improvement in pulmonary function and chronic bacterial infection was observed. Beta cell function and insulin clearance did not change in both treatment groups. Insulin sensitivity worsened in the Lumacaftor/Ivacaftor group. The analysis of vector plots confirmed that glucose regulation was stable in both groups. Conclusions: Treatment of CF patients with CFTR modulators does not significantly ameliorate glucose homeostasis and/or any of its direct determinants.

The thematic role of extracellular loop of VraG in activation of the membrane sensor GraS in a cystic fibrosis MRSA strain differs in nuance from the CA-MRSA strain JE2.

Patients with cystic fibrosis (CF) often suffer recurrent bronchial bacterial infections that lead to deterioration of lung function over time. The infections in CF patients are often due to S. aureus and P. aeruginosa that colonize the airways. Significantly, methicillin-resistant S. aureus (MRSA) makes it challenging for treatment in CF patients due to its feature of multiple antibiotic resistance. In bronchial airways, cationic antimicrobial peptides are often present in mucosa cells, neutrophils, and macrophages that interfere with bacterial proliferation. The major mechanism for resistance to the bactericidal activity of cationic peptides in S. aureus is mediated by the GraRS two-component system that activates expression of MprF and DltABCD to increase surface positive charge to repel interactions with cationic peptides. We recently found that VraG, a membrane permease component of the VraFG efflux pumps, harbors a long 200-residue extracellular loop (EL) that utilizes K380 to interact with the negatively charged 9-residue extracellular loop of the membrane sensor GraS to control mprF expression in a community-acquired MRSA strain JE2. In this study, we extended this observation to a CF MRSA strain CF32A1 where we affirmed that the EL loop of VraG controls GraS-mediated signal transduction; however, in contrast to community acquired MRSA strain JE2, the CF MRSA strain CF32A1 requires both K380 and K388 in the EL of VraG to properly modulate signal transduction mediated by GraS. This effect was not attributable to the several single nucleotide polymorphisms that exist between VraG and GraS in the two MRSA strains.

Brazilian Guidelines for Nutrition in Cystic Fibrosis.

ABSTRACTObjective To develop a scientific consensus on nutrition in cystic fibrosis.Methods Sixteen coordinators elaborated relevant questions on nutritional therapy in cystic fibrosis, which were divided into six sections: nutritional assessment, nutritional recommendations, nutritional intervention, dietary counseling, special situations and enzyme replacement, and gastrointestinal manifestations. Two to three specialists in the field were responsible for each section and obtaining answers formulated based on standardized bibliographic searches. The available literature was searched in the PubMed®/MEDLINE database, after training and standardization of search strategies, to write the best level of evidence for the questions elaborated. Issues related to disagreement were discussed until a consensus was reached among specialists, based on the current scientific literature.Results Forty-two questions were prepared and objectively answered, resulting in a consensus of nutritional therapy in cystic fibrosis.Conclusion This work enabled establishing a scientific consensus for nutritional treatment of cystic fibrosis patients.

Interleukin-1 beta is a potential mediator of airway nitric oxide deficiency in cystic fibrosis

Airway nitric oxide (NO) deficiency is a hallmark of cystic fibrosis (CF), but the reasons for the reduced NO production in CF airways are unclear. Interleukin (IL)-1 pathway activation plays a role in early CF lung disease and is also involved in the regulation of NO synthase activity. Treatment of CF patients with the CFTR-targeting drug ivacaftor, among other beneficial effects, results in an increase in airway NO levels. In this longitudinal observational trial, we show that ivacaftor therapy leads to a significant reduction in sputum IL-1β concentration but not in other IL-1- or Th17-associated cytokines. IL-1β concentrations were closely linked to improvement in pulmonary function, measures of NO metabolism in sputum and exhaled NO. These data therefore suggest a potential interaction between transepithelial chloride conductance, IL-1β and airway NO production.

Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene.

Cystic fibrosis (CF) is caused by loss of function of the CFTR chloride channel. A substantial number of CF patients carry nonsense mutations in the CFTR gene. These patients cannot directly benefit from pharmacological correctors and potentiators that have been developed for other types of CFTR mutations. We evaluated the efficacy of combinations of drugs targeting at various levels the effects of nonsense mutations: SMG1i to protect CFTR mRNA from nonsense-mediated decay (NMD), G418 and ELX-02 for readthrough, VX-809 and VX-445 to promote protein maturation and function, PTI-428 to enhance CFTR protein synthesis. We found that the extent of rescue and sensitivity to the various agents is largely dependent on the type of mutation, with W1282X and R553X being the mutations most and least sensitive to pharmacological treatments, respectively. In particular, W1282X-CFTR was highly responsive to NMD suppression by SMG1i but also required treatment with VX-445 corrector to show function. In contrast, G542X-CFTR required treatment with readthrough agents and VX-809. Importantly, we never found cooperativity between the NMD inhibitor and readthrough compounds. Our results indicate that treatment of CF patients with nonsense mutations requires a precision medicine approach with the design of specific drug combinations for each mutation.

CFTR modulation with elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis assessed by the β-adrenergic sweat rate assay

Background: The cystic fibrosis (CF) sweat gland is defective in β-adrenergically-stimulated sweat secretion in the coil and chloride reabsorption in the duct. Whereas chloride reabsorption is regularly assessed by quantitative pilocarpine iontophoresis (QPIT), the measurement of β-adrenergic sweat secretion is not yet established in clinical practice. Methods: A novel sweat bubble imaging protocol was developed that determines sweat secretion rates by automatic recording, processing and quality control of the kinetics of sweat droplet formation. Results: Treatment of CF patients with the CFTR modulators elexacaftor, tezacaftor and ivacaftor reduced the sweat chloride concentration measured in QPIT in the majority of patients to values in the intermediate or normal range. In contrast, the β-adrenergically-stimulated sweat secretion rate assayed by the automated bubble sweat test was normalized in only 3 patients, slightly increased in 12 patients and remained undetectable in 8 patients. Conclusions: β-adrenergic sweat stimulation in the coil is apparently rather stringent in its requirements for a wild type CFTR conformation whereas chloride reabsorption in the duct tolerates residual structural and functional deficits of native or pharmacologically rescued mutant CFTR in the apical membrane.

Antimicrobial Synergy Testing: Comparing the Tobramycin and Ceftazidime Gradient Diffusion Methodology Used in Assessing Synergy in Cystic Fibrosis-Derived Multidrug-Resistant Pseudomonas aeruginosa.

The need for synergy testing is driven by the necessity to extend the antimicrobial spectrum, reducing drug dosage/toxicity and the development of resistance. Despite the abundance of synergy testing methods, there is the absence of a gold standard and a lack of synergy correlation among methods. The most popular method (checkerboard) is labor-intensive and is not practical for clinical use. Most clinical laboratories use several gradient synergy methods which are quicker/easier to use. This study sought to evaluate three gradient synergy methods (direct overlay, cross, MIC:MIC ratio) with the checkerboard, and compare two interpretative criteria (the fractional inhibitory concentration index (FICI) and susceptibility breakpoint index (SBPI)) regarding these methods. We tested 70 multidrug-resistant Pseudomonas aeruginosa, using a tobramycin and ceftazidime combination. The agreement between the checkerboard and gradient methods was 60 to 77% for FICI, while agreements for SBPI that ranged between 67 and 82.86% were statistically significant (p ≤ 0.001). High kappa agreements were observed using SBPI (Ƙ > 0.356) compared to FICI (Ƙ < 0.291) criteria, and the MIC:MIC method demonstrated the highest, albeit moderate, intraclass correlation coefficient (ICC = 0.542) estimate. Isolate resistance profiles suggest method-dependent synergism for isolates, with ceftazidime susceptibility after increased exposure. The results show that when interpretative criteria are considered, gradient diffusion (especially MIC:MIC) is a valuable and practical method that can inform the treatment of cystic fibrosis patients who are chronically infected with P. aeruginosa.

Cost of therapy for cystic fibrosis in different age groups with consideration to the respiratory tract infection and complications

Despite the low prevalence of cystic fibrosis (CF), the costs of treating this disease are significant for the healthcare system. The aim of this economic study was to assess the total cost of drugs per year for children with CF, depending on age and course of the disease.Methods. For this pharmacoeconomic analysis, groups of “hypothetical” patients were formed according to the characteristics of the course of CF, taking into account the required volume of basic CF therapy, antibiotic therapy, and complications.Results. The cost of basic treatment for CF patients of different ages and disease progression in the hypothetical patient models can vary greatly. The cost of CF therapy increases significantly with age and Pseudomonas aeruginosa respiratory infection, especially in the patients with chronic infection, concomitant polyposis sinusitis, and low nutritional status.Conclusion. Patients with CF require regular follow-up with control of the microflora of the respiratory tract and effective eradication therapy for P. aeruginosa and other pathogenic microorganisms. Reducing infection rates and the severity of the disease can lead to significant cost savings.

Cystic Fibrosis: Recent Insights into Inhaled Antibiotic Treatment and Future Perspectives.

Although new inhaled antibiotics have profoundly improved respiratory diseases in cystic fibrosis (CF) patients, lung infections are still the leading cause of death. Inhaled antibiotics, i.e., colistin, tobramycin, aztreonam lysine and levofloxacin, are used as maintenance treatment for CF patients after the development of chronic Pseudomonas aeruginosa (P. aeruginosa) infection. Their use offers advantages over systemic therapy since a relatively high concentration of the drug is delivered directly to the lung, thus, enhancing the pharmacokinetic/pharmacodynamic parameters and decreasing toxicity. Notably, alternating treatment with inhaled antibiotics represents an important strategy for improving patient outcomes. The prevalence of CF patients receiving continuous inhaled antibiotic regimens with different combinations of the anti-P. aeruginosa antibiotic class has been increasing over time. Moreover, these antimicrobial agents are also used for preventing acute pulmonary exacerbations in CF. In this review, the efficacy and safety of the currently available inhaled antibiotics for lung infection treatment in CF patients are discussed, with a particular focus on strategies for eradicating P. aeruginosa and other pathogens. Moreover, the effects of long-term inhaled antibiotic therapy for chronic P. aeruginosa infection and for the prevention of pulmonary exacerbations is reviewed. Finally, how the mucus environment and microbial community richness can influence the efficacy of aerosolized antimicrobial agents is discussed.

Lumacaftor/ivacaftor changes the lung microbiome and metabolome in cystic fibrosis patients.

RationaleTargeted cystic fibrosis (CF) therapy with lumacaftor/ivacaftor partly restores chloride channel function and improves epithelial fluid transport in the airways. Consequently, changes may occur in the microbiome, which is adapted to CF lungs.ObjectivesTo investigate the effects of lumacaftor/ivacaftor on respiratory microbial composition and microbial metabolic activity by repeatedly sampling the lower respiratory tract.MethodsThis was a single-centre longitudinal observational cohort study in adult CF patients with a homozygous Phe508del mutation. Lung function measurements and microbial cultures of sputum were performed as part of routine care. An oral and nasal wash, and a breath sample, were collected before and every 3 months after starting therapy, for up to 12 months.ResultsTwenty patients were included in this study. Amplicon 16S RNA and metagenomics sequencing revealed that Pseudomonas aeruginosa was most abundant in sputum and seemed to decrease after 6 months of treatment, although this did not reach statistical significance after correction for multiple testing. Two types of untargeted metabolomics analyses in sputum showed a change in metabolic composition between 3 and 9 months that almost returned to baseline levels after 12 months of treatment. The volatile metabolic composition of breath was significantly different after 3 months and remained different from baseline until 12 months follow-up.ConclusionsAfter starting CF transmembrane conductance regulator (CFTR) modulating treatment in CF patients with a homozygous Phe508del mutation, a temporary and moderate change in the lung microbiome is observed, which is mainly characterised by a reduction in the relative abundance of Pseudomonas aeruginosa.

THE CORRELATION BETWEEN DEXA SCAN SCORES AND VITAMIN D LEVELS IN ADULTS WITH CYSTIC FIBROSIS

SESSION TITLE: Genetic and Developmental Disorders Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: In this retrospective chart review, the goal of the project was to determine if a correlation can be established between DEXA scan scores and Vitamin D levels in adults who have been diagnosed with cystic fibrosis. This study takes a variety of factors into account when trying to decipher if such correlation exists, including lifestyle, medical history, ethnicity, nutrition, etc. METHODS: Variables analyzed in the study include sex, age, BMI, CF genes, gene severity, CF modulators, PFT/EV1, sweat chloride, Vitamin D2 (ergocalciferol) levels, DEXA scan Z-score, time of DEXA scan, DEXA scan T-score, Vitamin D supplements and ethnicity. The densitometries were performed on the same machine. The data consisted of 23 males and 21 females, and the mean age was 37.7 years old, with a range of 22 to 57. Pulmonary function test (PFT) was used in conjunction with FEV1, the latter being a marker for cystic fibrosis and the former often used as a marker for a variety of pulmonary diseases including asthma, chronic obstructive pulmonary disorder, etc. The DEXA scan Z-score was taken from the lumbar spine of each patient. RESULTS: The correlation coefficient was determined to be -0.1491, which is indicative of a weak negative relationship between Vitamin D levels and DEXA scan scores. The P-value was calculated as 0.358221 and was deemed insignificant, therefore rejecting our null hypothesis. Analysis of the variables resulted in a mean Vitamin D level of 36.0 ng/mL and a mean DEXA Z-score of -1.2. The most common mutation observed was the F508del mutation. Patients can have two different mutations that cause cystic fibrosis including but not limited to N1303K, R1162X, G551D, L647P, 2185insA, etc. CONCLUSIONS: The correlation coefficient and P-value indicate that there is not a direct linear relationship between Vitamin D levels and DEXA scan scores in cystic fibrosis patients, hence rejecting our hypothesis that there is a direct linear relationship between the two respective variables. The results also confirmed that Vitamin D deficiency is not the only cause of decreased bone densitometry in CF patients. A larger sample size could have been obtained and more data could have been analyzed if access to the Cerner EHR was granted at an earlier time. In retrospect, perhaps other variables should have been focused on instead of Vitamin D levels and DEXA scans. Potential limitations in this study include difficulty obtaining access to the Cerner EHR and delay in obtaining a Vitamin D test after DEXA scan. CLINICAL IMPLICATIONS: This retrospective chart review has provided more insight in regard to various factors which may be correlated. Establishing a correlation between these factors may improve the quality of life and treatment of cystic fibrosis patients. Other variables which should be tested include sweat chloride levels and PFT results, as both vital in establishing care for cystic fibrosis patients. DISCLOSURES: No relevant relationships by Raufay Abbasi, source=Web Response Advisory Committee Member relationship with PARI Please note: $1001 - $5000 Added 03/31/2020 by Nauman Chaudary, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Novartis Please note: $1001 - $5000 Added 03/31/2020 by Nauman Chaudary, source=Web Response, value=Consulting fee No relevant relationships by Mannal Rahman, source=Web Response No relevant relationships by Moazan Rehman, source=Web Response

Cost-Effectiveness of Ivacaftor Therapy for Treatment of Cystic Fibrosis Patients With the G551D Gating Mutation.

Cystic fibrosis (CF) is a rare genetic disease with no cure. Until recently, treatment has targeted symptoms of the disease and not the disease-causing genetic defect. Ivacaftor is included in a new class of breakthrough drugs targeting the genetic defects of CF. We sought to estimate the long-term cost-effectiveness of ivacaftor from a US payer perspective. We developed an individual-level microsimulation model that followed a cohort of heterogeneous US CF patients over a lifetime. The primary outcome of interest was quality-adjusted life years (QALYs). We also compared unadjusted life years, count of acute pulmonary exacerbations, and count of lung transplants over a lifetime between patients treated with ivacaftor plus best supportive care and patients treated with best supportive care alone. We conducted one-way and probabilistic sensitivity analyses to test the impact of various model inputs and uncertainties. We found a substantial increase in QALYs, life years, and treatment costs over a lifetime for patients treated with ivacaftor plus best supportive care versus best supportive care alone. Discounted results for ivacaftor were 22.92 QALYs and $8 797 840 in total lifetime costs compared to 16.12 QALYs and $2 336 366 lifetime costs for best supportive care alone. The incremental cost-effectiveness ratios (ICERs) were $950 217 per QALY. Results from the probabilistic sensitivity analysis indicated a 0% chance that ivacaftor was cost-effective at a willingness-to-pay (WTP) threshold of $500 000 per QALY. Treatment with ivacaftor plus best supportive care versus best supportive care alone is not cost-effective at or near commonly accepted WTP thresholds.