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.
:
and
often infect the airways in cystic fibrosis (CF). Because registry studies show higher prevalence of
versus
in older patients with CF, a common assumption is that
replaces
over time.
,
can ...outgrow and kill
. However, it is unknown how rapidly
replaces
in patients with CF.
: We studied a longitudinal cohort of children and adults with CF who had quantitative sputum cultures. We determined the abundance of
and
in cfu/ml. We determined the duration and persistence of infections and measured longitudinal changes in culture positivity and abundance for each organism.
: Between 2004 and 2017, 134 patients had ≥10 quantitative cultures, with median observation time of 10.15 years. One hundred twenty-four patients had at least one positive culture for
, and 123 had at least one positive culture for
. Both species had median abundance of >10
cfu/ml. Culture abundance was stable over time for both organisms. There was an increase in the prevalence of
/
coinfection but no decrease in
prevalence within individuals over time.
:
and
are abundant in CF sputum cultures. Contrary to common assumption, we found no pattern of replacement of
by
. Many patients with CF have durable long-term coinfection with these organisms. New strategies are needed to prevent and treat these infections.
Background
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have shown beneficial effects on both forced expiratory volume in 1 s (FEV1) and frequency of pulmonary exacerbations ...in people with cystic fibrosis (CF). These positive outcomes may be related to changes in bacterial colonization within the lungs. Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is the first triple therapy CFTR modulator approved for use in people with CF 6 years and older. This study aimed to determine the impact of ELX/TEZ/IVA on the isolation of Pseudomonas aeruginosa (Pa), methicillin‐resistant and methicillin‐susceptible Staphylococcus aureus (MRSA and MSSA, respectively) in respiratory cultures.
Methods
A retrospective chart review of the electronic medical record at the University of Iowa was completed for individuals 12 years and older taking ELX/TEZ/IVA for at least 12 months. The primary outcome was determined by assessing bacterial cultures pre‐ and postinitiation of ELX/TEZ/IVA. Baseline demographic and clinical characteristics were summarized using mean and standard deviation for continuous outcomes and count and percentage for categorical outcomes. Culture positivity for Pa, MSSA, and MRSA was compared among enrolled subjects between pre‐ and posttriple combination therapy periods using an exact McNemar's test.
Results
One hundred and twenty‐four subjects prescribed ELX/TEZ/IVA for at least 12 months met the requirements for inclusion within our analysis. Culture positivity for Pa, MSSA, and MRSA was approximately 54%, 33%, and 31%, respectively, for the pre‐ELX/TEZ/IVA period. Prevalence decreased to approximately 30%, 32%, and 24% (−24.2% p < 0.0001, −0.7% p = 1.00, and −6.5% p = 0.0963, respectively) post‐ELX/TEZ/IVA. The source of bacterial culture was predominantly sputum (70.2%) in the pre‐ELX/TEZ/IVA group, whereas a throat source (66.1%) was more common post‐ELX/TEZ/IVA.
Conclusions
ELX/TEZ/IVA treatment has an appreciable impact on the detection of common bacterial pathogens in CF respiratory cultures. While previous studies have found a similar effect with single and double CFTR modulator therapies, this is the first single‐center study to show the impact of triple therapy, ELX/TEZ/IVA, on bacterial isolation from airway secretions.
Background
Cystic fibrosis (CF) is a multisystem disorder that results in the buildup of mucus in various organs. Ninety percent of CF patients are classified as pancreatic insufficient, leading to ...malabsorption of nutrients and fat‐soluble vitamins without the assistance of exogenous pancreatic enzymes. This study was designed to determine if serum 25‐hydroxyvitamin D concentrations were impacted by initiation of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA).
Methods
Serum 25‐hydroxyvitamin D concentrations were measured before and 1 year post‐ELX/TEZ/IVA initiation. A Wilcoxon signed‐rank test was used to compare values.
Results
Seventy‐six patients were included in the final analysis. The average age of our population was 25.8 years (SD = 13.2 years) with a majority being male, homozygous F508del, pancreatic insufficient, and not modulator‐naive. The median increase of serum vitamin D concentration after initiating ELX/TEZ/IVA was 5 ng/ml (interquartile range = −4, 13; p = .0035).
Conclusions
We suggest that ELX/TEZ/IVA may improve fat‐soluble vitamin absorption, specifically serum 25‐hydroxyvitamin D. These results may lead to adjustments in vitamin supplementation in patients receiving cystic fibrosis transmembrane conductance regulator modulator therapy.
Background
This study was undertaken to determine if a clinically relevant drug‐drug interaction occurred between ibuprofen and lumacaftor/ivacaftor.
Methods
Peak ibuprofen plasma concentrations were ...measured prior to and after lumacaftor/ivacaftor initiation. A Wilcoxon signed rank sum test was used to compare the values.
Results
Nine patients were included in the final analysis. Peak ibuprofen plasma concentrations decreased an average of 36.4 mcg/mL after initiation of lumacaftor/ivacaftor with a relative reduction of 41.7%. The average peak plasma concentration was 84.2 mcg/mL (SD = 10.9) prior to lumacaftor/ivacaftor initiation and 47.9 mcg/mL (SD = 16.4) following initiation (P = 0.0039). Peak concentrations occurred at an average of 100 min (SD = 30) and 107 min (SD = 40) prior to and following lumacaftor/ivacaftor initiation, respectively.
Conclusions
We suggest a clinically relevant drug‐drug interaction exists between ibuprofen and lumacaftor/ivacaftor. Lumacaftor may cause subtherapeutic ibuprofen plasma concentrations due to the induction of CYP enzymes and increased metabolism of ibuprofen. Based on this analysis, we have modified our use of ibuprofen in several patients after evaluation of this drug‐drug interaction.
is a highly prevalent respiratory pathogen in cystic fibrosis (CF). It is unclear how this organism establishes chronic infections in CF airways. We hypothesized that
isolates from patients with CF ...would share common virulence properties that enable chronic infection.
77
isolates were obtained from 45 de-identified patients with CF at the University of Iowa. We assessed isolates phenotypically and used genotyping assays to determine the presence or absence of 18 superantigens (SAgs).
We observed phenotypic diversity among
isolates from patients with CF. Genotypic analysis for SAgs revealed 79.8% of CF clinical isolates carried all six members of the enterotoxin gene cluster (EGC). MRSA and MSSA isolates had similar prevalence of SAgs. We additionally observed that EGC SAgs were prevalent in
isolated from two geographically distinct CF centers.
SAgs belonging to the EGC are highly prevalent in CF clinical isolates. The greater prevalence in these SAgs in CF airway specimens compared to skin isolates suggests that these toxins confer selective advantage in the CF airway.
Introduction. Cystic Fibrosis Foundation guidelines recommend people with CF perform daily airway clearance. This can be difficult for patients, as some find it time consuming or uncomfortable. Data ...comparing airway clearance methods are limited. We surveyed patients and their families to understand which methods are preferred and identify obstacles to performing airway clearance. Methods. We designed a REDCap survey and enrolled participants in 2021. Respondents reported information on airway clearance usage, time commitment, and medication use. They rated airway clearance methods for effectiveness, comfort, time commitment, importance, and compatibility with other treatments. The analysis included descriptive statistics and clustering. Results. 60 respondents started and 52 completed the survey. The median patient age was 20 years. Respondents experienced a median of four airway clearance methods in their lifetime, including chest wall oscillation (vest, 92%), manual chest physical therapy (CPT, 88%), forced expiration technique (huff or cough, 77%), and exercise (75%). Past 30-day use was highest for exercise (62%) and vest (57%). The time commitment was generally less than 2 hours daily. Of those eligible for CFTR modulators, 53% reported decreased time commitment to airway clearance after starting treatment. On a scale of 0–100, respondents rated CFTR modulators as their most important treatment (median 99.5), followed by exercise (88). Discussion. Patients and caregivers are familiar with several methods of airway clearance for CF. They report distinct strengths and limitations of each method. Exercise and vest are the most common methods of airway clearance. The use of CFTR modulators may reduce patient-reported time commitment to airway clearance.
Background
The cystic fibrosis transmembrane conductance regulator (CFTR) modulators ivacaftor and lumacaftor/ivacaftor improve the status of existing infections in patients with cystic fibrosis ...(CF). It is unknown how well these drugs protect patients against incident infections. We hypothesized that CFTR modulator treatment would decrease new infections with Pseudomonas aeruginosa or Staphylococcus aureus.
Methods
We retrospectively studied a single‐center cohort of patients with CF during two time periods (2008‐2011, Era 1) and (2012‐2015, Era 2) based on the January 2012 approval of ivacaftor. Using Kaplan–Meier analysis, we compared the time to any new infection with P. aeruginosa, methicillin‐resistant
S. aureus (MRSA), or methicillin‐sensitive
S. aureus (MSSA) that was absent during a 2‐year baseline. We stratified the analysis based on whether patients received ivacaftor or lumacaftor/ivacaftor during Era 2. We used the log‐rank test and considered
P < 0.05 statistically significant.
Results
For patients receiving ivacaftor or lumacaftor/ivacaftor in Era 2, there was a statistically significant delay in the time to new bacterial acquisition in Era 2 vs. Era 1 (
P = 0.008). For patients who did not receive CFTR modulators, there was a trend toward slower acquisition of new bacterial infections in Era 2 compared to Era 1, but this was not statistically significant (
P = 0.10).
Conclusions
Patients receiving ivacaftor or lumacaftor/ivacaftor for CF had significantly delayed acquisition of
P. aeruginosa and
S. aureus after these drugs were released. This method for analyzing incident infections may be useful for future studies of CFTR modulators and bacterial acquisition in CF registry cohorts.
Background
This study was undertaken to determine if the presence of a clinical pharmacy team impacted patients’ access to cystic fibrosis transmembrane conductance regulator (CFTR) modulators.
...Methods
A retrospective chart review of electronic medical records from the University of Iowa Hospitals and Clinics (UIHC) was conducted. Data were collected regarding the timing of prior authorization (PA) submissions and approvals from 2012 to 2018. The Wilcoxon rank‐sum test was used to compare the meantime (days) between prescription and PA submission dates, and PA submission and approval date for all patients included in the analysis. Comparisons were made for pre‐ and postpharmacy services eras as well as the UIHC Specialty Pharmacy versus a non‐UIHC Specialty Pharmacy.
Results
Sixty‐three patients were included in the final analysis. The average time between prescription date and PA submission was 12.5 days (standard deviation SD = 17.4 days) in the preclinical pharmacy services era and 3.5 days (SD = 5.8 days; P = .028) in the postclinical pharmacy services era. The average time to PA submission significantly decreased from 9.8 days (SD = 13.1 days) to 1.3 days (SD = 4.2 days; P < .0001) when prescriptions were filled by the UIHC Specialty Pharmacy vs a non‐UIHC Specialty Pharmacy.
Conclusions
There was a significant benefit to CFTR modulator prescribing when clinical pharmacy services were incorporated in our cystic fibrosis (CF) care team, which will become increasingly important with the anticipation of new CF medications in the near future.
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