Impact of chronic medication de-escalation in patients with cystic fibrosis taking elexacaftor, tezacaftor, ivacaftor: A retrospective review.

BACKGROUND: This single-center, retrospective study evaluated the effects of de-escalating cystic fibrosis (CF) supportive therapies in patients on elexacaftor/tezacaftor/ivacaftor (ETI). For many with CF, the clinical benefit of ETI exceeds that of supportive therapies. Therefore, we anticipated patients would desire to discontinue many of their supportive therapies, leading to the creation of a de-escalation algorithm. If patients were clinically improved and stable on ETI, CF supportive therapies could be de-escalated quarterly in accordance with the algorithm. METHODS: The primary objective was to assess non-inferiority of supportive therapies de-escalation by comparing the absolute change in percent predicted (ppFEV1) from baseline to month 1 versus the absolute change from baseline to month 12 after initiating ETI with patients serving as their own control. A chart review of patients initiated on ETI from September 2019 through December 2020 was conducted. Inclusion criteria included those six years and older with at least one copy of F508del. RESULTS: The study included 174 patients. The mean ppFEV1 at baseline, month 1, and month 12 was 67%, 78%, and 87% respectively. The mean difference in absolute change in ppFEV1 from baseline to month 1 compared to baseline to month 12 after the initiation of ETI was 1.53% (95% CI: -0.49 to 3.55) CONCLUSION: De-escalating supportive therapies for those on ETI was non-inferior to remaining on all supportive therapies. This suggests that medications may be able to be discontinued under the context of a de-escalation algorithm, which may decrease medication burden and cost and increase quality of life.

The Diagnostic Error Index: A Quality Improvement Initiative to Identify and Measure Diagnostic Errors.

OBJECTIVE: To develop a diagnostic error index (DEI) aimed at providing a practical method to identify and measure serious diagnostic errors. STUDY DESIGN: A quality improvement (QI) study at a quaternary pediatric medical center. Five well-defined domains identified cases of potential diagnostic errors. Identified cases underwent an adjudication process by a multidisciplinary QI team to determine if a diagnostic error occurred. Confirmed diagnostic errors were then aggregated on the DEI. The primary outcome measure was the number of monthly diagnostic errors. RESULTS: From January 2017 through June 2019, 105 cases of diagnostic error were identified. Morbidity and mortality conferences, institutional root cause analyses, and an abdominal pain trigger tool were the most frequent domains for detecting diagnostic errors. Appendicitis, fractures, and nonaccidental trauma were the 3 most common diagnoses that were missed or had delayed identification. CONCLUSIONS: A QI initiative successfully created a pragmatic approach to identify and measure diagnostic errors by utilizing a DEI. The DEI established a framework to help guide future initiatives to reduce diagnostic errors.

Practitioner Due Diligence: Real-World Lumacaftor/Ivacaftor Use.

OBJECTIVE: Previous trials evaluated the efficacy of lumacaftor/ivacaftor in Phe508del homozygotes. These trials are limited by manufacturer sponsorship and were conducted under strict protocol. Additionally, this therapy is costly and does not allow for reduction in daily cystic fibrosis therapies. This study assessed the efficacy of lumacaftor/ivacaftor therapy and its effect on health care utilization in a real-world setting. METHODS: Retrospective chart review comparing the first 12 months of therapy to the 24 months prior was conducted to evaluate the impact of lumacaftor/ivacaftor on pulmonary function following a streamlined process for therapy introduction. The impact on body mass index and healthcare utilization were also evaluated. The following measurements were assessed: percent predicted forced expiratory volume in 1 second, body mass index and z-scores, number of admissions, length of stay, number of emergency department visits. RESULTS: Mean ppFEV1 was improved for the first 12 months on lumacaftor/ivacaftor treatment when compared with the 24 months prior: 78.8 (95% CI: 72.6, 84.9) vs 76.2 (95% CI: 70.1, 82.3) (p = 0.03). Body mass index significantly improved (patients ≥20 years), but improvement in BMI z-score (patients <20 years) was not significant. Number of admissions and LOS were significantly decreased, but ED visits were not. CONCLUSIONS: Lumacaftor/ivacaftor is effective for improving ppFEV1 and BMI and for reducing health care utilization. However, this small reduction does not overcome the financial cost of treatment. Long-term outcomes and use must be studied to determine the overall effect of this therapy on cystic fibrosis interventions and their costs.

Identification of Mycobacterium porcinum in patients with cystic Fibrosis: Pathogen or contaminant?

BACKGROUND: Mycobacterium porcinum is a non-tuberculous mycobacterium (NTM) identified in potable water. The identification and clinical impact of M. porcinum in patients with cystic fibrosis (CF) has not been described. In our institution, M. porcinum was isolated exclusively during hospitalization in a cluster of patients with CF. METHODS: Patients with CF who were hospitalized between September 2016 and September 2018 and could expectorate sputum were included, and samples were processed per institutional guidelines. Post-hospitalization and one-year clinical outcomes on those who isolated M. porcinum in respiratory cultures were reviewed. Whole genome sequencing was performed on M. porcinum isolates obtained from patients and environmental sources to identify source of acquisition. RESULTS: Review of 14 CF patients with 16 M. porcinum isolates revealed rapid time to culture positivity within 0.8 (0.04-8.0) days after admission. M. porcinum was isolated in teenagers and adults irrespective of baseline pulmonary function, body mass index, or CF genotype. Whole genome sequencing suggested all isolates belong to the same M. porcinum strain and confirmed the source of acquisition to the ice machine. Review of patients' clinical course, including three patients who underwent lung transplantation, suggested a pseudo-outbreak with minimal clinical impact. CONCLUSIONS: NTM, including M. porcinum, are ubiquitous in potable water and institutional water reservoirs. Our findings suggest M. porcinum is a transient colonizer rather than a pathogen. Challenges exist in discerning the role of NTM as a contributor of pulmonary morbidity in patients with CF, and adherence to established guidelines regarding NTM related pulmonary disease remains important.

Meropenem time above the MIC exposure is predictive of response in cystic fibrosis children with acute pulmonary exacerbations.

Meropenem exposures from 15 children (8-17 years old) with cystic fibrosis (CF) acute pulmonary exacerbation were analyzed to define the pharmacodynamic threshold required for a positive response. The primary endpoint was the relative increase in forced expiratory volume in 1 s (↑FEV1) between pre- and posttreatment. Meropenem pharmacodynamic indices (fT > MIC, fAUC/MIC, fCmin/MIC) over the first 24 h were estimated for each participant based on their individual parameter estimates and the isolated pathogen with the highest meropenem MIC. Pseudomonas aeruginosa was the most common pathogen (n = 11/15). The mean ± SD ↑FEV1 was 18.8% ± 11.3% posttreatment. The mean (range) fT > MIC exposure was 63% (0-100%). An Emax model determined a significant relationship between fT > MIC and ↑FEV1 (r2 = 0.8, P < 0.0004). 65% fT > MIC was a significant predictor of response; the median (25th, 75th %) ↑FEV1 was 28.5% (22.2%, 31.7%) in those patients who achieved above 65% fT > MIC and 7.8% (1.1%, 12.6%) in those at or below 65% fT > MIC (P = 0.001). This is the first study in CF children to link meropenem exposure with a positive response as measured by ↑FEV1. Larger studies are required to confirm this exposure threshold.

Correction to: Immunosuppression Drug Therapy in Lung Transplantation for Cystic Fibrosis.

In the print publication the name of the seventh author was incorrectly published.

Immunosuppression Drug Therapy in Lung Transplantation for Cystic Fibrosis.

Cystic fibrosis (CF) is a common indication for lung transplantation (LTx) in children and adults with severe and irreversible lung disease. In the setting of LTx in the CF population, immunosuppressive medications are used to prevent allograft rejection despite the majority of these patients being chronically infected with numerous, and often antibiotic-resistant, pathogens. There is limited evidence for the optimal post-LTx immunosuppression regimen in patients with CF, particularly in children. This article provides a review of immunosuppression regimens in the pediatric and adult CF post-LTx population, investigating drug dosing and monitoring, and medication combinations. Currently used immunosuppressive medications and related systemic adverse effects are reviewed. With limitations of data in the pediatric population, future research should address immunosuppression in these children to help guide pediatric drug management as a means to optimize clinical outcomes after LTx.

Population pharmacokinetics of meropenem administered as a prolonged infusion in children with cystic fibrosis.

OBJECTIVES: Meropenem is frequently used to treat pulmonary exacerbations in children with cystic fibrosis (CF) in the USA. Prolonged-infusion meropenem improves the time that free drug concentrations remain above the MIC (fT> MIC) in adults, but data in CF children are sparse. We describe the population pharmacokinetics, tolerability and treatment burden of prolonged-infusion meropenem in CF children. METHODS: Thirty children aged 6-17 years with a pulmonary exacerbation received 40 mg/kg meropenem every 8 h; each dose was administered as a 3 h infusion. Pharmacokinetics were determined using population methods in Pmetrics. Monte Carlo simulation was employed to compare 0.5 with 3 h infusions to estimate the probability of pharmacodynamic target attainment (PTA) at 40% fT> MIC. NCT#01429259. RESULTS: A two-compartment model fitted the data best with clearance and volume predicted by body weight. Clearance and volume of the central compartment were 0.41 ±â€Š0.23 L/h/kg and 0.30 ±â€Š0.17 L/kg, respectively. Half-life was 1.11 ±â€Š0.38 h. At MICs of 1, 2 and 4 mg/L, PTAs for the 0.5 h infusion were 87.6%, 70.1% and 35.4%, respectively. The prolonged infusion increased PTAs to >99% for these MICs and achieved 82.8% at 8 mg/L. Of the 30 children, 18 (60%) completed treatment with prolonged infusion; 5 did so at home without any reported burden. Nine patients were changed to a 0.5 h infusion when discharged home. CONCLUSIONS: In these CF children, meropenem clearance was greater compared with published values from non-CF children. Prolonged infusion provided an exposure benefit against pathogens with MICs ≥1 mg/L, was well tolerated and was feasible to administer in the hospital and home settings, the latter depending on perception and family schedule.

Microbiological activity of ceftolozane/tazobactam, ceftazidime, meropenem, and piperacillin/tazobactam against Pseudomonas aeruginosa isolated from children with cystic fibrosis.

The activity of ceftolozane/tazobactam was tested against 50 nonduplicate Pseudomonas aeruginosa from 18 cystic fibrosis children collected in 2012-2014. These isolates were multidrug resistant with susceptibility to meropenem, ceftazidime, and piperacillin/tazobactam of 46%, 58%, and 50%, respectively. Ceftolozane/tazobactam was the most active with MIC50, MIC90, and percent susceptibility of 2mg/L, 8 mg/L, and 86%.

Hypotension following cardiac surgery associated with paroxetine and mirtazapine withdrawal.

This case describes a 15-year-old patient who experienced postoperative hypotension following an elective Ross procedure for aortic stenosis/insufficiency. The patient was taking paroxetine and mirtazapine for depression which were held prior to surgery. Hypotension occurred approximately eight hours postoperatively and required vasopressor support. Upon reinitiation of antidepressant therapy, hypotension resolved and vasopressor support was discontinued. A year later the patient required conduit replacement, and antidepressant therapy was weaned off during the three weeks prior to surgery. No hypotension was observed following the second surgery. Paroxetine withdrawal has been well-documented within adult literature, but there is little information regarding mirtazapine withdrawal. Furthermore, cardiovascular effects have not been well-documented, and even less is known within the pediatric population. Withdrawal symptoms in these agents may be explained by cholinergic rebound and/or rapid decline in serum concentrations upon abrupt discontinuation. It may be reasonable to consider tapering antidepressants with short half-lives prior to elective surgery in which patients may not be able to take maintenance medications for more than 24 hours.