Sex differences in outcomes of people with cystic fibrosis treated with elexacaftor/tezacaftor/ivacaftor.

BACKGROUND: There is a well described sex-disparity in outcomes of individuals with cystic fibrosis (CF), with females faring worse than males. Given the dramatic improvement in overall health of people with CF using CF transmembrane conductance regulator (CFTR) modulator therapy, elexacaftor/tezacaftor/ivacaftor (ETI), the sex-disparity in CF warrants re-examination. METHODS: We evaluated the effects of ETI use by sex prior to versus after initiation of ETI by pulmonary exacerbations (PEx), percent predicted forced expiratory volume in one second (ppFEV1), presence of Pseudomonas aeruginosa in sputum cultures, and body mass index (BMI). We used univariate and multivariable longitudinal regression adjusting for key confounders, such as age, race, CFTR modulator taken prior to ETI and baseline ppFEV1. RESULTS: We included 251 individuals started on ETI between January 2014 to September 2022. We collected data for a mean of 5.45 years pre-ETI and 2.38 years post-ETI. We found the adjusted presence of PEx decreased more in males than females pre- to post-ETI with the odds of having a PEx in males being 0.57 (43% reduction) versus females 0.75 (25% reduction) (p = 0.049). We found no statistical difference by sex for ppFEV1, presence of Pseudomonas aeruginosa or BMI pre- to post-ETI by sex. CONCLUSION: After treatment with ETI, there was a greater decline in PEx in males versus females. Long-term impact of ETI by sex is still unknown, but we will need to seek ways to effectively tailor care for individuals with CF and consider pharmacokinetic studies of ETI comparing males to females.

Genomic epidemiology of Mycobacterium abscessus at an adult cystic fibrosis programme reveals low potential for healthcare-associated transmission.

Rationale: Nontuberculous mycobacteria (NTM) has been reported to be transmitted between people with cystic fibrosis (CF) attending CF centres. A suspected Mycobacterium abscessus outbreak was investigated at the University of Texas Southwestern (UTSW) Adult CF Program using a combination of pathogen genomic sequencing and epidemiologic methods. The objectives of the present study were to apply the Healthcare-Associated Links in Transmission of NTM (HALT NTM) study to investigate the occurrence of potential healthcare-associated transmission and/or acquisition of NTM among people with CF infected with genetically similar NTM isolates. Methods: Whole-genome sequencing of respiratory M. abscessus isolates from 50 people with CF receiving care at UTSW was performed to identify genetically similar isolates. Epidemiologic investigation, comparison of respiratory and environmental isolates, and home residence watershed mapping were studied. Measurements and main results: Whole-genome sequencing analysis demonstrated seven clusters of genetically similar M. abscessus (four ssp. abscessus and three ssp. massiliense). Epidemiologic investigation revealed potential opportunities for healthcare-associated transmission within three of these clusters. Healthcare environmental sampling did not recover M. abscessus, but did recover four human disease-causing species of NTM. No subjects having clustered infections lived in the same home residence watershed. Some subjects were infected with more than one M. abscessus genotype, both within and outside of the dominant circulating clones. Conclusions: Healthcare-associated person-to-person transmission of M. abscessus appears to be rare at this centre. However, polyclonal infections of M. abscessus species and subspecies, not originating from the endemic hospital environment, suggest multiple shared modes of acquisition outside the healthcare setting.

Ceftaroline versus vancomycin for treatment of acute pulmonary exacerbations of cystic fibrosis in adults.

OBJECTIVES: Vancomycin remains a first-line treatment for methicillin-resistant Staphylococcus aureus (MRSA)-mediated acute pulmonary exacerbations (APEs) in adult cystic fibrosis (CF) patients; however, optimal alternatives remain poorly defined. The aim of this study was to determine the safety and efficacy of ceftaroline for MRSA-mediated APEs of CF in adults. METHODS: We conducted a retrospective, observational cohort study comparing ceftaroline with vancomycin for the treatment of MRSA-mediated APEs in adult CF patients. The primary endpoint was the return to at least 90% of baseline lung function measured by discharge FEV1% predicted in comparison with baseline FEV1% predicted. RESULTS: A total of 55 patients were included in the analysis (22 receiving ceftaroline and 33 receiving vancomycin). Of the patients included in the analysis, 13 patients (59%) in the ceftaroline group and 24 patients (73%) in the vancomycin group met the primary outcome (P = 0.38). FEV1 measurements at baseline, admission and discharge were not different between treatments. Secondary outcomes including 30-day re-admission rate, 30-day mortality, treatment duration and adverse events (neutropenia, Clostridioides difficile infection and acute kidney injury) were similar between groups. CONCLUSION: Our small cohort study supports ceftaroline as an alternative treatment option for MRSA-mediated APE of CF in adults.

In vitro activity of ceftolozane-tazobactam and ceftazidime-avibactam against Pseudomonas aeruginosa isolated from patients with cystic fibrosis.

Pseudomonas aeruginosa is a commonly isolated pathogen in adults with cystic fibrosis (CF). Antimicrobial resistance is an escalating problem due to chronic colonization and frequent antimicrobial exposure. Ceftolozane-tazobactam (C/T) and ceftazidime-avibactam (CZA) exhibit promising activity against antimicrobial resistant organisms, including P. aeruginosa. A retrospective review was conducted comparing the in vitro activities of C/T and CZA against 42 P. aeruginosa isolates from the respiratory tract of 32 adults with CF. The first isolate per patient per year that underwent susceptibility testing for C/T, CZA, and colistin was included. C/T was more susceptible than CZA (60% versus 43%). Thirty-eight (90%) isolates were considered highly drug resistant and demonstrated higher C/T susceptibilities compared to CZA (55% versus 45%). These results suggest using C/T while awaiting susceptibilities when standard antipseudomonal agents cannot be used.

End-of-Life Care in Cystic Fibrosis: Comparing Provider Practices Based on Lung Transplant Candidacy.

Background: The optimal timing to introduce palliative care (PC) and end-of-life (EOL) conversations into the lives of people with cystic fibrosis (CF) has not been established. Objective: Compare EOL care practices for people with CF who died without a lung transplant (LT), are living without an LT, and those who received an LT. Design: Retrospective chart review. Setting/Subjects: People with CF who received care from 2012 to 2017 at the University of Texas Southwestern Medical Center. Measurements: Primary outcomes were (1) EOL discussion with a pulmonologist, (2) time of EOL discussion before death or LT, (3) evaluation by PC, and (4) documentation of advanced directive or medical power of attorney. Results: Twenty-three patients died without LT, 40 patients received an LT, and 222 were living without an LT. Among LT recipients, 10% had EOL conversations compared with 74% of deceased patients and 5% of living patients without LT (p = 0.001). Among deceased patients, 39% had EOL conversations more than six months before death, while 5% of transplanted patients had EOL conversation more than six months before LT (p < 0.001). Deceased patients were more likely to have seen PC (57%) than either patients who received LT (2%) or those living without LT (3%, p = 0.0001). Conclusions: Patients who died without LT were more likely to have seen PC and had an EOL conversation than patients who received LT or who are living without LT. Further research should explore the optimal timing to discuss EOL care and the best timing to involve PC.

Ceftolozane/tazobactam sensitivity patterns in Pseudomonas aeruginosa isolates recovered from sputum of cystic fibrosis patients.

Ceftolozane/tazobactam is a combination intravenous antibiotic with potentially important activity against drug-resistant Gram-negative organisms. Ceftolozane/tazobactam's in vitro activity was evaluated in 30 samples collected from 23 adult cystic fibrosis patients with extended and pan-resistant Pseudomonas aeruginosa in 2015. Testing results demonstrated that 30% of the isolates were susceptible,13% were intermediate, and 57% were resistant. This suggests that ceftolozane/tazobactam may be a useful antibiotic in carefully selected, multidrug-resistant Pseudomonas isolates.

Multidrug-resistant Pseudomonas aeruginosa from sputum of patients with cystic fibrosis demonstrates a high rate of susceptibility to ceftazidime-avibactam.

PURPOSE: Ceftazidime-avibactam is a novel antimicrobial combining a third-generation cephalosporin with a non-ß-lactam ß-lactamase inhibitor that was recently approved to treat Gram-negative hospital- and ventilator-acquired pneumonia. The use of ceftazidime-avibactam to treat Pseudomonas aeruginosa respiratory infections in patients with cystic fibrosis (CF) has not been evaluated. In this study, we assessed the ceftazidime-avibactam susceptibility of multidrug-resistant (MDR) P. aeruginosa sputum isolates from adults with CF. METHODS: Sputum was collected from individuals with CF, aged ≥18 years, known to be colonized with MDR P. aeruginosa, and tested for susceptibility to 11 different antipseudomonal antimicrobial agents. Isolates were included in the analysis if they were resistant to both ceftazidime and at least one agent in ≥3 different antimicrobial categories routinely used to treat P. aeruginosa. Subject demographics and clinical characteristics were collected. Ceftazidime-avibactam-resistant isolates were screened for the presence of ß-lactam-resistant mechanisms. RESULTS: Thirty-two P. aeruginosa isolates were analyzed, of which 23 isolates were sensitive to ceftazidime-avibactam (71.9%). Ten of the isolates were mucoid and 22 isolates were nonmucoid, both demonstrating >70% susceptibility to ceftazidime-avibactam. The most notable difference in the subjects with resistant strains was an older age and lower body mass index (BMI). Ceftazidime-avibactam-resistant strains showed elevated AmpC expression in >60% of the strains and loss of OprD detection in >70% of the strains. CONCLUSION: Ceftazidime-avibactam demonstrated a significant in vitro activity against highly resistant P. aeruginosa sputum isolates from individuals with CF. Further evaluation of the cause of resistance and clinical impact of ceftazidime-avibactam in CF patients with MDR P. aeruginosa is warranted.

Evaluating Simulation-Based ACLS Education on Patient Outcomes: A Randomized, Controlled Pilot Study.

BACKGROUND: Simulation training is widely accepted as an effective teaching tool, especially for dealing with high-risk situations. OBJECTIVE: We assessed whether standardized, simulation-based advanced cardiac life support (ACLS) training improved performance in managing simulated and actual cardiac arrests. METHODS: A total of 103 second- and third-year internal medicine residents were randomized to 2 groups. The first group underwent conventional ACLS training. The second group underwent two 2 1/2-hour sessions of standardized simulation ACLS teaching. The groups were assessed by evaluators blinded to their assignment during in-hospital monthly mock codes and actual inpatient code sheets at 3 large academic hospitals. Primary outcomes were time to initiation of cardiopulmonary resuscitation, time to administration of first epinephrine/vasopressin, time to delivery of first defibrillation, and adherence to American Heart Association guidelines. RESULTS: There were no differences in primary outcomes among the study arms and hospital sites. During 21 mock codes, the most common error was misidentification of the initial rhythm (67% [6 of 9] and 58% [7 of 12] control and simulation arms, respectively, P  =  .70). There were no differences in primary outcome among groups in 147 actual inpatient codes. CONCLUSIONS: This blinded, randomized study found no effect on primary outcomes. A notable finding was the percentage of internal medicine residents who misidentified cardiac arrest rhythms.

Vitamin D and chronic lung disease: a review of molecular mechanisms and clinical studies.

Vitamin D is classically recognized for its role in calcium homeostasis and skeletal metabolism. Over the last few decades, vitamin D deficiency has increased in prevalence in adults and children. Potential extraskeletal effects of vitamin D have been under investigation for several diseases. Several cross-sectional studies have associated lower vitamin D status with decreased lung function. This finding has prompted investigators to examine the association of vitamin D deficiency with several chronic lung diseases. One major focus has been the link between maternal vitamin D status and childhood asthma. Vitamin D deficiency has also been associated with increased risk of respiratory infection from influenza A and Mycobacterium tuberculosis. Other chronic respiratory diseases associated with vitamin D deficiency include cystic fibrosis, interstitial lung disease, and chronic obstructive pulmonary disease. This review will examine the current clinical literature and potential mechanisms of vitamin D in various pulmonary diseases.

Predictors of mortality in hospitalized patients with acute exacerbation of bronchiectasis.

BACKGROUND: In-hospital and long term outcomes of patients admitted to the hospital for acute exacerbation of bronchiectasis (AEB) has been evaluated in only a limited fashion. The resulting debilitation after an AEB can increase mortality. This study aims to evaluate the factors associated with mortality in patients admitted with an acute exacerbation of bronchiectasis (AEB). METHODS: All charts of the patients admitted between 2003 and 2006 with an AEB were reviewed through an electronic database. Demographics, sputum cultures, pulmonary functions tests and other factors associated with long-term mortality were examined. The social security death index was used to determine long term mortality (http://ssdi.genealogy.rootsweb.com). RESULTS: Forty-three patients (13 men and 30 women) with a mean age of 71.8+/-11.8 were studied. The hospital mortality was 9% and one-year mortality was 30% with a median survival of 46.6 months. Variables associated with mortality were male gender (female vs. male (HR), 0.36; (CI), 0.14-0.98; p=0.045), use of systemic steroids (with vs. without steroids HR, 3.12; CI 1.08-9.02; p=0.036), decreased FEV(1.0)% predicted (HR, 0.96; CI 0.92-0.999; p=0.042), elevated creatinine (HR, 2.36; CI 1.093-5.10; p=0.029), history of smoking (HR, 0.283; CI 0.097-0.825; p=0.021), and mechanical ventilation (HR, 66.011; CI 6.64-656.76; p=0.0004). CONCLUSIONS: Male gender, elevated creatinine, decreased FEV(1.0)% predicted, mechanical ventilation, history of smoking, and acute use of systemic steroids during the hospitalization were associated with an increased risk of mortality.