Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in People with Cystic Fibrosis: A Clinical Trial.

Rationale: The cystic fibrosis (CF) modulator drug, elexacaftor/tezacaftor/ivacaftor (ETI), proved highly effective in controlled clinical trials for individuals with at least one F508del allele, which occurs in at least 85% of people with CF. Objectives: PROMISE is a postapproval study to understand the broad effects of ETI through 30 months' clinical use in a more diverse U.S. patient population with planned analyses after 6 months. Methods: Prospective, observational study in 487 people with CF age 12 years or older with at least one F508del allele starting ETI for the first time. Assessments occurred before and 1, 3, and 6 months into ETI therapy. Outcomes included change in percent predicted FEV1 (ppFEV1), sweat chloride concentration, body mass index (BMI), and self-reported respiratory symptoms. Measurements and Main Results: Average age was 25.1 years, and 44.1% entered the study using tezacaftor/ivacaftor or lumacaftor/ivacaftor, whereas 6.7% were using ivacaftor, consistent with F508del homozygosity and G551D allele, respectively. At 6 months into ETI therapy, ppFEV1 improved 9.76 percentage points (95% confidence interval [CI], 8.76 to 10.76) from baseline, cystic fibrosis questionnaire-revised respiratory domain score improved 20.4 points (95% CI, 18.3 to 22.5), and sweat chloride decreased -41.7 mmol/L (95% CI, -43.8 to -39.6). BMI also significantly increased. Changes were larger in those naive to modulators but substantial in all groups, including those treated with ivacaftor at baseline. Conclusions: ETI by clinical prescription provided large improvements in lung function, respiratory symptoms, and BMI in a diverse population naive to modulator drug therapy, using existing two-drug combinations, or using ivacaftor alone. Each group also experienced significant reductions in sweat chloride concentration, which correlated with improved ppFEV1 in the overall study population. Clinical trial registered with www.clinicaltrials.gov (NCT NCT04038047).

Testing the effects of combining azithromycin with inhaled tobramycin for P. aeruginosa in cystic fibrosis: a randomised, controlled clinical trial.

RATIONALE: Inhaled tobramycin and oral azithromycin are common chronic therapies in people with cystic fibrosis and Pseudomonas aeruginosa airway infection. Some studies have shown that azithromycin can reduce the ability of tobramycin to kill P. aeruginosa. This trial was done to test the effects of combining azithromycin with inhaled tobramycin on clinical and microbiological outcomes in people already using inhaled tobramycin. We theorised that those randomised to placebo (no azithromycin) would have greater improvement in forced expiratory volume in one second (FEV1) and greater reduction in P. aeruginosa sputum in response to tobramycin. METHODS: A 6-week prospective, randomised, placebo-controlled, double-blind trial testing oral azithromycin versus placebo combined with clinically prescribed inhaled tobramycin in individuals with cystic fibrosis and P. aeruginosa airway infection. RESULTS: Over a 6-week period, including 4 weeks of inhaled tobramycin, the relative change in FEV1 did not statistically significantly differ between groups (azithromycin (n=56) minus placebo (n=52) difference: 3.44%; 95% CI: -0.48 to 7.35; p=0.085). Differences in secondary clinical outcomes, including patient-reported symptom scores, weight and need for additional antibiotics, did not significantly differ. Among the 29 azithromycin and 35 placebo participants providing paired sputum samples, the 6-week change in P. aeruginosa density differed in favour of the placebo group (difference: 0.75 log10 CFU/mL; 95% CI: 0.03 to 1.47; p=0.043). CONCLUSIONS: Despite having greater reduction in P. aeruginosa density in participants able to provide sputum samples, participants randomised to placebo with inhaled tobramycin did not experience significantly greater improvements in lung function or other clinical outcomes compared with those randomised to azithromycin with tobramycin.

Association Between Number of Intravenous Antipseudomonal Antibiotics and Clinical Outcomes of Pediatric Cystic Fibrosis Pulmonary Exacerbations.

BACKGROUND: Pulmonary exacerbations (PEx) in people with cystic fibrosis (PwCF) are associated with significant morbidity. While standard PEx treatment for PwCF with Pseudomonas aeruginosa infection includes two IV antipseudomonal antibiotics, little evidence exists to recommend this approach. This study aimed to compare clinical outcomes of single versus double antipseudomonal antibiotic use for PEx treatment. METHODS: Retrospective cohort study using the linked CF Foundation Patient Registry-Pediatric Health Information System dataset. PwCF were included if hospitalized between 2007 and 2018 and 6-21 years of age. Regression modeling accounting for repeated measures was used to compare lung function outcomes between single versus double IV antipseudomonal antibiotic regimens using propensity-score weighting to adjust for relevant confounding factors. RESULTS: Among 10,660 PwCF in the dataset, we analyzed 2,578 PEx from 1,080 PwCF, of which 455 and 2,123 PEx were treated with 1 versus 2 IV antipseudomonal antibiotics, respectively. We identified no significant differences between PEx treated with 1 versus 2 IV antipseudomonal antibiotics either in change between pre- and post-PEx percent predicted forced expiratory volume in one second (ppFEV1) (-0.84%, [95% CI -2.25, 0.56]; P = 0.24), odds of returning to ≥90% of baseline ppFEV1 within 3 months following PEx (Odds Ratio 0.83, [95% CI 0.61, 1.13]; P = 0.24) or time to next PEx requiring IV antibiotics (Hazard Ratio 1.04, [95% CI 0.87, 1.24]; P = 0.69). CONCLUSIONS: Use of 2 IV antipseudomonal antibiotics for PEx treatment in young PwCF was not associated with greater improvements in measured respiratory and clinical outcomes compared to treatment with 1 IV antipseudomonal antibiotic.

Changing Rates of Chronic Pseudomonas aeruginosa Infections in Cystic Fibrosis: A Population-Based Cohort Study.

Background: Chronic Pseudomonas aeruginosa lung infection is associated with significant morbidity and mortality in cystic fibrosis (CF). It is not known whether recent advances in care have affected the rates of chronic infection. We aimed to determine if the rates of developing new chronic P. aeruginosa infection among adolescents and adults with CF significantly changed over time. Methods: The cohort consisted of individuals with CF followed in the Cystic Fibrosis Foundation Patient Registry aged ≥13 years without chronic P. aeruginosa at baseline. Multivariable regression models accounting for within-patient correlation were used to assess the change in rate of developing chronic P. aeruginosa infection between 2003 and 2012. Results: A total of 15504 individuals were followed for a median of 5 (interquartile range, 2-9) years. The annual rates of developing new chronic P. aeruginosa decreased from 14.3% in 2003 to 6.4% in 2012. After adjusting for potential confounders, relative risk (RR) of developing chronic P. aeruginosa infection decreased significantly over time compared to 2003 (P value test of trend < .001). Compared with 2003, the RR of developing chronic P. aeruginosa infection in 2012 was 0.33 (95% confidence interval, 0.30-0.37). No significant increases in risk of chronic infections with other major CF bacterial pathogens relative to 2003 were identified. Conclusions: Among individuals with CF, a significant decrease in the risk and rates of developing chronic P. aeruginosa infection between 2003 and 2012 was observed. Whether this decline results in changes in clinical outcomes warrants further exploration.

Airway Progenitor Clone Formation Is Enhanced by Y-27632-Dependent Changes in the Transcriptome.

The application of conditional reprogramming culture (CRC) methods to nasal airway epithelial cells would allow more wide-spread incorporation of primary airway epithelial culture models into complex lung disease research. In this study, we adapted the CRC method to nasal airway epithelial cells, investigated the growth advantages afforded by this technique over standard culture methods, and determined the cellular and molecular basis of CRC cell culture effects. We found that the CRC method allowed the production of 7.1 × 10(10) cells after 4 passages, approximately 379 times more cells than were generated by the standard bronchial epithelial growth media (BEGM) method. These nasal airway epithelial cells expressed normal basal cell markers and could be induced to form a mucociliary epithelium. Progenitor cell frequency was significantly higher using the CRC method in comparison to the standard culture method, and progenitor cell maintenance was dependent on addition of the Rho-kinase inhibitor Y-27632. Whole-transcriptome sequencing analysis demonstrated widespread gene expression changes in Y-27632-treated basal cells. We found that Y-27632 treatment altered expression of genes fundamental to the formation of the basal cell cytoskeleton, cell-cell junctions, and cell-extracellular matrix (ECM) interactions. Importantly, we found that Y-27632 treatment up-regulated expression of unique basal cell intermediate filament and desmosomal genes. Conversely, Y-27632 down-regulated multiple families of protease/antiprotease genes involved in ECM remodeling. We conclude that Y-27632 fundamentally alters cell-cell and cell-ECM interactions, which preserves basal progenitor cells and allows greater cell amplification.

Antiinflammatory and Antimicrobial Effects of Thiocyanate in a Cystic Fibrosis Mouse Model.

Thiocyanate (SCN) is used by the innate immune system, but less is known about its impact on inflammation and oxidative stress. Granulocytes oxidize SCN to evolve the bactericidal hypothiocyanous acid, which we previously demonstrated is metabolized by mammalian, but not bacterial, thioredoxin reductase (TrxR). There is also evidence that SCN is dysregulated in cystic fibrosis (CF), a disease marked by chronic infection and airway inflammation. To investigate antiinflammatory effects of SCN, we administered nebulized SCN or saline to ß epithelial sodium channel (ßENaC) mice, a phenotypic CF model. SCN significantly decreased airway neutrophil infiltrate and restored the redox ratio of glutathione in lung tissue and airway epithelial lining fluid to levels comparable to wild type. Furthermore, in Pseudomonas aeruginosa-infected ßENaC and wild-type mice, SCN decreased inflammation, proinflammatory cytokines, and bacterial load. SCN also decreased airway neutrophil chemokine keratinocyte chemoattractant (also known as C-X-C motif chemokine ligand 1) and glutathione sulfonamide, a biomarker of granulocyte oxidative activity, in uninfected ßENaC mice. Lung tissue TrxR activity and expression increased in inflamed lung tissue, providing in vivo evidence for the link between hypothiocyanous acid metabolism by TrxR and the promotion of selective biocide of pathogens. SCN treatment both suppressed inflammation and improved host defense, suggesting that nebulized SCN may have important therapeutic utility in diseases of both chronic airway inflammation and persistent bacterial infection, such as CF.

Drug interactions and treatment burden as survival improves.

PURPOSE OF REVIEW: With our growing understanding of the pathophysiology of cystic fibrosis, the pace of drug discovery is accelerating. Newer agents and therapies have traditionally been added to available medications, given the urgency in treating the disease. As the cystic fibrosis population ages, the number of associated comorbidities increases, requiring additional therapeutic approaches. Thus, while current management strategies have dramatically extended projected life expectancy, the treatment burden of the disease in adulthood has become onerous, and there is increasing concern over unintended effects and drug-drug interactions of new and existing therapies. RECENT FINDINGS: A number of recent studies have sought to quantify the treatment burden of cystic fibrosis care, and to identify ways to reduce this burden. Mechanistic studies have identified the potential for a number of cystic fibrosis medications to impair the host response, or to interfere with the efficacy of other agents. SUMMARY: As the cystic fibrosis formulary grows, a primary emphasis will be for providers to develop personalized treatment plans, with a goal to reduce unnecessary treatment burden and an awareness of potential unanticipated effects of medications.

Selective metabolism of hypothiocyanous acid by mammalian thioredoxin reductase promotes lung innate immunity and antioxidant defense.

The endogenously produced oxidant hypothiocyanous acid (HOSCN) inhibits and kills pathogens but paradoxically is well tolerated by mammalian host tissue. Mammalian high molecular weight thioredoxin reductase (H-TrxR) is evolutionarily divergent from bacterial low molecular weight thioredoxin reductase (L-TrxR). Notably, mammalian H-TrxR contains a selenocysteine (Sec) and has wider substrate reactivity than L-TrxR. Recombinant rat cytosolic H-TrxR1, mouse mitochondrial H-TrxR2, and a purified mixture of both from rat selectively turned over HOSCN (kcat = 357 ± 16 min(-1); Km = 31.9 ± 10.3 µM) but were inactive against the related oxidant hypochlorous acid. Replacing Sec with Cys or deleting the final eight C-terminal peptides decreased affinity and turnover of HOSCN by H-TrxR. Similarly, glutathione reductase (an H-TrxR homologue lacking Sec) was less effective at HOSCN turnover. In contrast to H-TrxR and glutathione reductase, recombinant Escherichia coli L-TrxR was potently inhibited by HOSCN (IC50 = 2.75 µM). Similarly, human bronchial epithelial cell (16HBE) lysates metabolized HOSCN, but E. coli and Pseudomonas aeruginosa lysates had little or no activity. HOSCN selectively produced toxicity in bacteria, whereas hypochlorous acid was nonselectively toxic to both bacteria and 16HBE. Treatment with the H-TrxR inhibitor auranofin inhibited HOSCN metabolism in 16HBE lysates and significantly increased HOSCN-mediated cytotoxicity. These findings demonstrate both the metabolism of HOSCN by mammalian H-TrxR resulting in resistance to HOSCN in mammalian cells and the potent inhibition of bacterial L-TrxR resulting in cytotoxicity in bacteria. These data support a novel selective mechanism of host defense in mammals wherein HOSCN formation simultaneously inhibits pathogens while sparing host tissue.

Enhanced in vitro formation and antibiotic resistance of nonattached Pseudomonas aeruginosa aggregates through incorporation of neutrophil products.

Pseudomonas aeruginosa is a major pathogen in cystic fibrosis (CF) lung disease. Children with CF are routinely exposed to P. aeruginosa from the natural environment, and by adulthood, 80% of patients are chronically infected. P. aeruginosa in the CF airway exhibits a unique biofilm-like structure, where it grows in small clusters or aggregates of bacteria in association with abundant polymers of neutrophil-derived components F-actin and DNA, among other components. These aggregates differ substantially in size and appearance compared to surface-attached in vitro biofilm models classically utilized for studies but are believed to share properties of surface-attached biofilms, including antibiotic resistance. However, little is known about the formation and function of surface-independent modes of biofilm growth, how they might be eradicated, and quorum sensing communication. To address these issues, we developed a novel in vitro model of P. aeruginosa aggregates incorporating human neutrophil-derived products. Aggregates grown in vitro and those found in CF patients' sputum samples were morphologically similar; viable bacteria were distributed in small pockets throughout the aggregate. The lasA quorum sensing gene was differentially expressed in the presence of neutrophil products. Importantly, aggregates formed in the presence of neutrophils acquired resistance to tobramycin, which was lost when the aggregates were dispersed with DNase, and antagonism of tobramycin and azithromycin was observed. This novel yet simple in vitro system advances our ability to model infection of the CF airway and will be an important tool to study virulence and test alternative eradication strategies against P. aeruginosa.

Longitudinal improvements in clinical and functional outcomes following initiation of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis.

Background: Use of elexacaftor/tezacaftor/ivacaftor (ETI) for treatment of cystic fibrosis (CF) has resulted in unprecedented clinical improvements necessitating development of outcome measures for monitoring disease course. Intranasal micro-optical coherence tomography (µOCT) has previously helped detect and characterize mucociliary abnormalities in patients with CF. This study was done to determine if µOCT can define the effects of ETI on nasal mucociliary clearance and monitor changes conferred to understand mechanistic effects of CFTR modulators beyond CFTR activation. Methods: 26 subjects, with at least 1 F508del mutation were recruited and followed at baseline (visit 1), +1 month (visit 2) and +6 months (visit 4) following initiation of ETI therapy. Clinical outcomes were computed at visits 1, 2 and 4. Intranasal µOCT imaging and functional metrics analysis including mucociliary transport rate (MCT) estimation were done at visits 1 and 2. Results: Percent predicted forced expiratory volume in 1 s (ppFEV1) showed a significant increase of +10.9 % at visit 2, which sustained at visit 4 (+10.6 %). Sweat chloride levels significantly decreased by -36.6 mmol/L and -41.3 mmol/L at visits 2 and 4, respectively. µOCT analysis revealed significant improvement in MCT rate (2.8 ± 1.5, visit 1 vs 4.0 ± 1.5 mm/min, visit 2; P = 0.048). Conclusions: Treatment with ETI resulted in significant and sustained clinical improvements over 6 months. Functional improvements in MCT rate were evident within a month after initiation of ETI therapy indicating that µOCT imaging is sensitive to the treatment effect of HEMT and suggests improved mucociliary transport as a probable mechanism of action underlying the clinical benefits.

The cost of simplifying treatments for cystic fibrosis: Implications of the SIMPLIFY trial.

BACKGROUND: Dornase alfa and hypertonic saline are mucoactive therapies that can improve respiratory symptoms in people with cystic fibrosis (CF). A recent randomized control trial showed that participants with well-preserved pulmonary function taking elexacaftor + tezacaftor + ivacaftor (ETI) who discontinued dornase alfa or hypertonic saline for 6 weeks had no clinically meaningful decline in lung function. This may prompt discussions with care providers regarding ongoing use of these medications. OBJECTIVE: To compare the costs of outpatient medications between people taking ETI who continued or discontinued (1) dornase alfa or (2) hypertonic saline from 2 clinical trials and project cost differences in the US CF population if these 2 medications were used only intermittently for symptom relief instead of chronically. METHODS: The SIMPLIFY study was 2 parallel multicenter trials that randomized participants 1:1 to either continue or discontinue therapy. To estimate costs, we used data from the Merative MarketScan Databases to identify people with CF from 2020 to 2021. Our primary outcomes were differences in costs of outpatient prescription drugs among those who continued vs discontinued dornase alfa and, separately, hypertonic saline. We obtained adjusted differences in median costs. To estimate the annual cost savings if the population of people with CF taking ETI used these medications only intermittently, we multiplied the proportion of people in MarketScan with CF diagnoses who were taking each of these medications by the median cost savings per year and subtracted the cost of "rescue" use. RESULTS: A total of 392 participants from the dornase alfa trial and 273 from the hypertonic saline trial were included in analyses. The adjusted difference in median medication costs was not significant for the hypertonic saline trial, but we observed a significantly decreased 6-week cost of medications in the dornase alfa trial (adjusted median difference in costs between discontinue and continue of $5,860 (95% CI = $4,870-$6,850); P < 0.0001). We estimated that two-thirds of people with CF use ETI and dornase alfa in the United States; if they discontinued dornase alfa except for intermittent use, the resulting annual savings would be $1.21 billion. CONCLUSIONS: Although the costs of dornase alfa and hypertonic saline are smaller compared with ETI, reduction in use would lead to substantial prescription drug cost savings and reduce the treatment burden. However, individual benefits of these therapies should be considered, and decisions regarding changes in therapy remain an important discussion between people with CF and their providers. Study registration number: NCT04378153.

The effect of discontinuing hypertonic saline or dornase alfa on mucociliary clearance in elexacaftor/tezacaftor/ivacaftor treated people with cystic fibrosis: The SIMPLIFY-MCC Study.

Many people with CF (pwCF) desire a reduction in inhaled treatment burden after initiation of elexacaftor/tezacaftor/ivacaftor. The randomized, open-label SIMPLIFY study showed that discontinuing hypertonic saline (HS) or dornase alfa (DA) was non-inferior to continuation of each treatment with respect to change in lung function over a 6-week period. In this SIMPLIFY substudy, we used gamma scintigraphy to determine whether discontinuation of either HS or DA was associated with deterioration in the rate of in vivo mucociliary clearance (MCC) in participants ≥12 years of age. While no significant differences in MCC endpoints were associated with HS discontinuation, significant improvement in whole and peripheral lung MCC was observed after discontinuing DA. These results suggest that pwCF on ETI with mild lung disease do not experience a subclinical deterioration in MCC that could later impact health outcomes after discontinuing HS, and in fact may benefit from improved MCC after stopping DA treatment.

Prospective evaluation of nontuberculous mycobacteria disease in cystic fibrosis: The design of the PREDICT study.

BACKGROUND: Nontuberculous mycobacteria (NTM) are an important cause of airway infections in people with cystic fibrosis (pwCF). Isolation of NTM from respiratory specimens of pwCF do not mandate treatment in the absence of clinical and radiologic features of NTM pulmonary disease (NTM-PD), as some pwCF clear the infection without treatment and others do not appear to progress to NTM-PD despite persistent infection. An evidence-based protocol to standardize diagnosis of NTM-PD is needed to systematically identify pwCF who may benefit from treatment. METHODS: In this multicenter observational study, eligible pwCF who are 6 years of age and older and who have had a recent positive NTM culture are systematically evaluated for NTM-PD. Participants are identified based on positive NTM culture results obtained during routine clinical care and following enrollment are evaluated for NTM-PD and CF-related comorbidities. Participants are followed in PREDICT until they meet NTM-PD diagnostic criteria and are ready to initiate NTM treatment, or until study termination. Active participants who have not met these criteria are re-consented every 5 years to enable long-term participation. RESULTS: The primary endpoint will summarize the proportion of participants who meet the NTM-PD diagnosis definition. The time from enrollment to NTM-PD diagnosis will be derived from Kaplan-Meier estimates. CONCLUSION: A prospective protocol to identify NTM-PD in pwCF will test if this standardized approach defines a cohort with signs and symptoms associated with NTM-PD, to assist with clinical decision making and to build a framework for future therapeutic trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02073409.

Effect of elexacaftor/tezacaftor/ivacaftor on mucus and mucociliary clearance in cystic fibrosis.

BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (E/T/I) is highly effective clinically for those with at least one F508del-CFTR allele. The effects of E/T/I on mucociliary clearance (MCC) and sputum properties are unknown. We, therefore, sought to characterize the effects of E/T/I on in vivo MCC and sputum characteristics hypothesized to impact mucus transport. METHODS: Forty-four participants ≥12 years of age were enrolled into this prospective, observational trial prior to initiation of E/T/I and had baseline measurement of MCC and characterization of induced sputum and exhaled breath condensate (EBC) samples. Study procedures were repeated after 1 month of E/T/I treatment. RESULTS: Average age was 27.7 years with baseline forced expiratory volume in 1 second (FEV1) of 78.2 % predicted. 52 % of subjects had previously been treated with a 2-drug CFTR modulator combination. The average whole lung MCC rate measured over 60 min (WLAveClr60) significantly improved from baseline to post-E/T/I (14.8 vs. 22.8 %; p = 0.0002), as did other MCC indices. Sputum% solids also improved (modeled mean 3.4 vs. 2.2 %; p<0.0001), whereas non-significant reductions in sputum macrorheology (G', G") were observed. No meaningful changes in exhaled breath condensate endpoints (sialic acid:urea ratio, pH) were observed. CONCLUSIONS: E/T/I improved the hydration of respiratory secretions (% solids) and markedly accelerated MCC. These data confirm the link between CFTR function, mucus solid content, and MCC and help to define the utility of MCC and mucus-related bioassays in future efforts to restore CFTR function in all people with CF.

Effects of azithromycin in Pseudomonas aeruginosa burn wound infection.

BACKGROUND: Cutaneous thermal injuries (i.e., burns) remain a common form of debilitating trauma, and outcomes are often worsened by wound infection with environmental bacteria, chiefly Pseudomonas aeruginosa. MATERIALS AND METHODS: We tested the effects of early administration of a single dose of azithromycin, with or without subsequent antipseudomonal antibiotics, in a mouse model of standardized thermal injury infected with P aeruginosa via both wound site and systemic infection. We also tested the antimicrobial effects of these antibiotics alone or combined in comparative biofilm and planktonic cultures in vitro. RESULTS: In our model, early azithromycin administration significantly reduced wound and systemic infection without altering wound site or circulating neutrophil activity. The antimicrobial effect of azithromycin was additive with ciprofloxacin but significantly reduced the antimicrobial effect of tobramycin. This pattern was reproduced in biofilm cultures and not observed in planktonic cultures of P aeruginosa. CONCLUSION: These data suggest that early administration of azithromycin following burn-related trauma and infection may reduce P aeruginosa infection and potential interactions with other antibiotics should be considered when designing future studies.

The impact of elexacaftor/tezacaftor/ivacaftor on fat-soluble vitamin levels in people with cystic fibrosis.

BACKGROUND: While elexacaftor/tezacaftor/ivacaftor (ETI) has improved the pulmonary health of many people with cystic fibrosis (PwCF), less is known about ETI effectiveness for extra-pulmonary manifestations, including fat-soluble vitamin malabsorption. This study aims to evaluate ETI's impact on vitamin A, D, E, and international normalized ratio (INR, an indirect marker for Vitamin K) serum levels. METHODS: Retrospective cohort study of PwCF ≥12 years receiving ETI. Vitamin levels up to four years preceding and up to two years following ETI initiation were collected. Pairwise comparisons of vitamin levels pre/post-ETI initiation were made using Wilcoxon signed rank and McNemar's tests. Linear mixed effect models were used to regress vitamin levels on time since starting ETI, ETI use (yes/no), the interaction between time and ETI use, and age. RESULTS: Two hundred and sixty-four participants met study inclusion, and 169 (64%) had post-ETI initiation vitamin levels. Median vitamin A levels increased from 422.0 to 471.0 mcg/L (p < 0.001), median vitamin D levels increased from 28.5 to 30.8 ng/mL (p = 0.003), and there were no significant changes in median vitamin E or INR. Vitamin A levels rose at a rate of 40.7 mcg/L/year (CI 11.3, 70.2) after ETI start. CONCLUSIONS: ETI initiation is associated with increased median vitamin A and vitamin D levels, but no change in median vitamin E or INR levels. Ongoing monitoring of vitamin levels after ETI initiation is needed to screen for potential deficiencies and toxicities, particularly in light of case reports of hypervitaminosis A following ETI initiation.

Polymicrobial infections and antibiotic treatment patterns for cystic fibrosis pulmonary exacerbations.

BACKGROUND: No data exist to guide antibiotic selection among people with CF (PwCF) with respiratory cultures positive for multiple CF-related bacteria (polymicrobial infections). This study aimed to describe the number of polymicrobial in-hospital treated pulmonary exacerbations (PEx), to determine the proportion of polymicrobial PEx where antibiotics were prescribed with activity against all bacteria detected (termed complete antibiotic coverage), and to determine clinical and demographic factors associated with complete antibiotic coverage. METHODS: Retrospective cohort study using the CF Foundation Patient Registry-Pediatric Health Information System dataset. Children aged 1-21 years with an in-hospital treated PEx from 2006 to 2019 were eligible for inclusion. Bacterial culture positivity was based on any positive respiratory culture in the 12 months prior to a study PEx. RESULTS: A total of 4,923 children contributed 27,669 total PEx of which 20,214 were polymicrobial; of these, 68% of PEx had complete antibiotic coverage. In regression modeling, a prior PEx with complete antibiotic coverage for MRSA was associated with a higher likelihood of having complete antibiotic coverage at a subsequent study PEx (OR (95% CI) 3.48 (2.50, 4.83)). CONCLUSIONS: The majority of children with CF hospitalized for polymicrobial PEx were prescribed complete antibiotic coverage. Prior PEx treatment with complete antibiotic coverage predicted complete antibiotic coverage at a future PEx for all bacteria studied. Studies are needed comparing outcomes of polymicrobial PEx treated with different antibiotic coverages to optimize PEx antibiotic selection.

Pharmacologic improvement of CFTR function rapidly decreases sputum pathogen density, but lung infections generally persist.

BackgroundLung infections are among the most consequential manifestations of cystic fibrosis (CF) and are associated with reduced lung function and shortened survival. Drugs called CF transmembrane conductance regulator (CFTR) modulators improve activity of dysfunctional CFTR channels, which is the physiological defect causing CF. However, it is unclear how improved CFTR activity affects CF lung infections.MethodsWe performed a prospective, multicenter, observational study to measure the effect of the newest and most effective CFTR modulator, elexacaftor/tezacaftor/ivacaftor (ETI), on CF lung infections. We studied sputum from 236 people with CF during their first 6 months of ETI using bacterial cultures, PCR, and sequencing.ResultsMean sputum densities of Staphylococcus aureus, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Achromobacter spp., and Burkholderia spp. decreased by 2-3 log10 CFU/mL after 1 month of ETI. However, most participants remained culture positive for the pathogens cultured from their sputum before starting ETI. In those becoming culture negative after ETI, the pathogens present before treatment were often still detectable by PCR months after sputum converted to culture negative. Sequence-based analyses confirmed large reductions in CF pathogen genera, but other bacteria detected in sputum were largely unchanged. ETI treatment increased average sputum bacterial diversity and produced consistent shifts in sputum bacterial composition. However, these changes were caused by ETI-mediated decreases in CF pathogen abundance rather than changes in other bacteria.ConclusionsTreatment with the most effective CFTR modulator currently available produced large and rapid reductions in traditional CF pathogens in sputum, but most participants remain infected with the pathogens present before modulator treatment.Trial RegistrationClinicalTrials.gov NCT04038047.FundingThe Cystic Fibrosis Foundation and the NIH.