Inhaled Medications for Maintenance Therapy in Pediatric Noncystic Fibrosis Bronchiectasis.

OBJECTIVE: This review focuses on evaluating literature for the use of inhaled mucolytics (hypertonic saline, mannitol, and dornase alfa), inhaled antibiotics (tobramycin, aztreonam, colistin, and amikacin), and inhaled corticosteroids in pediatric noncystic fibrosis bronchiectasis. DATA SOURCES: A literature search via PubMed was conducted using the search terms "non-cystic fibrosis bronchiectasis," "primary ciliary dyskinesia," and "bronchiectasis" in combination with each inhaled agent of interest. STUDY SELECTION AND DATA EXTRACTION: Studies were included if they were specific to patients with a clinical diagnosis of noncystic fibrosis bronchiectasis published from 1998 to July 2024. DATA SYNTHESIS: Several inhaled medications can be considered as maintenance therapies for pediatric patients with noncystic fibrosis bronchiectasis. Hypertonic saline could be considered for its potential airway clearance benefits and low risk of causing harm. Inhaled antipseudomonal antibiotics should be considered in patients who are colonized with Pseudomonas aeruginosa. Inhaled corticosteroid therapy should be reserved for patients with concomitant asthma. Dornase alfa has shown worse outcomes in adults with noncystic fibrosis bronchiectasis and should be used with caution. Risks and benefits should be carefully considered when evaluating these therapies for use in noncystic fibrosis bronchiectasis, and patient-specific treatment regimens should be developed. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Chronic management of pediatric noncystic fibrosis bronchiectasis remains challenging due to paucity of applicable literature. Risks and benefits of different agents are discussed in this article with recommendations for application to clinical practice based on studies performed in both adult and pediatric patients with noncystic fibrosis bronchiectasis. CONCLUSION: Several inhaled medications could be considered as maintenance therapies for pediatric patients with noncystic fibrosis bronchiectasis, with more robust evidence to support use of inhaled antipseudomonal antibiotics and hypertonic saline compared with other available agents. Further investigation is needed to identify a clear place in therapy for inhaled therapies in pediatric noncystic fibrosis bronchiectasis.

Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary Exacerbation.

Adults with cystic fibrosis (CF) frequently harbor Staphylococcus aureus, which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant S. aureus Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients (n = 18) admitted for exacerbations received 3 doses of telavancin 7.5 mg/kg of body weight (first 6 patients) or 10 mg/kg (final 12 patients) every 24 h (q24h). Population pharmacokinetic models with and without covariates were fitted using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5,000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing the volume of distribution of the central compartment (Vc ) as a multiple of total body weight (TBW) and the volume of distribution of the central compartment scaled to total body weight (Vθ) normalized by the median observed value (Vc = Vθ × TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL = CLNR + CLθ × CRCL), where CLNR represents nonrenal clearance and CLθ represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: Vθ, 4.92 ± 0.76 liters · kg-1; CLNR, 0.59 ± 0.30 liters · h-1; CLθ, 5.97 × 10-3 ± 1.24 × 10-3; Vp (volume of the peripheral compartment), 3.77 ± 1.41 liters; Q (intercompartmental clearance), 4.08 ± 2.17 liters · h-1 The free area under the concentration-time curve (fAUC) values for 7.5 and 10 mg/kg were 30 ± 4.6 and 52 ± 12 mg · h/liter, respectively. Doses of 7.5 mg/kg and 10 mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a fAUC/MIC threshold of >215, respectively, for MIC of ≤0.12 mg/liter. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763 mg · h · liter-1) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10 mg/kg yielded optimal PTA and minimal risk of AKI, suggesting that this FDA-approved dose is appropriate to treat acute pulmonary exacerbations in CF adults. (The clinical trial discussed in this study has been registered at ClinicalTrials.gov under identifier NCT03172793.).

Population Pharmacokinetics and Safety of Ceftolozane-Tazobactam in Adult Cystic Fibrosis Patients Admitted with Acute Pulmonary Exacerbation.

Ceftolozane-tazobactam has potent activity against Pseudomonas aeruginosa, a pathogen associated with cystic fibrosis (CF) acute pulmonary exacerbations (APE). Due to the rapid elimination of many antibiotics, CF patients frequently have altered pharmacokinetics. In this multicenter, open-label study, we described the population pharmacokinetics and safety of ceftolozane-tazobactam at 3 g every 8 h (q8h) in 20 adult CF patients admitted with APE. Population pharmacokinetics were determined using the nonparametric adaptive grid program in Pmetrics for R. A 5,000-patient Monte Carlo simulation was performed to determine the probability of target attainment (PTA) for the ceftolozane component at 1.5 g and 3 g of ceftolozane-tazobactam q8h across a range of MICs using a primary threshold exposure of 60% free time above the MIC (fT>MIC). In these 20 adult CF patients, ceftolozane and tazobactam concentration data were best described by 2-compartment models, and ceftolozane clearance (CL) was significantly correlated with creatinine clearance (r = 0.71, P < 0.001). These data suggest that ceftolozane and tazobactam clearance estimates in CF patients are similar to those in adults without CF (ceftolozane CF CL, 4.76 ± 1.13 liter/h; tazobactam CF CL, 20.51 ± 4.41 liter/h). However, estimates of the volume of the central compartment (Vc) were lower than those for adults without CF (ceftolozane CF Vc, 7.51 ± 2.05 liters; tazobactam CF Vc, 7.85 ± 2.66 liters). Using a threshold of 60% fT>MIC, ceftolozane-tazobactam regimens of 1.5 g and 3 g q8h should achieve PTAs of ≥90% at MICs up to 4 and 8 µg/ml, respectively. Ceftolozane-tazobactam at 3 g q8h was well tolerated. These observations support additional studies of ceftolozane-tazobactam for Pseudomonas aeruginosa APE in CF patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02421120.).

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.

Prevalence of depression and antidepressant therapy use in a pediatric cystic fibrosis population.

BACKGROUND: Depression is associated with significant morbidity and mortality. In recent years reports of depression in cystic fibrosis (CF) patients of all ages have increased. As awareness of depression in CF increases, there remains limited data regarding the prevalence and management of depression in the pediatric CF population. OBJECTIVES: To assess the prevalence of depression, describe depression treatment regimens, and identify risk factors for depression in the pediatric CF population at a single care center. METHODS: A retrospective chart review was conducted on 190 patients at 1 accredited CF center. Patient demographics and clinical characteristics were collected and compared between patients with depression and patients without depression. In addition, the treatment strategies of patients with depression were recorded. RESULTS: The number of patients with a documented diagnosis of depression was found to be 9%, and 50% of these patients were prescribed antidepressant therapy. The most common class of medication prescribed for depression in these patients was the selective serotonin reuptake inhibitors, where fluoxetine was the most common medication. Patients with depression had a lower mean absolute forced expiratory volume in 1 s (1.88 vs 2.48 L; P = .042), more than 5 total hospitalizations per year (4 vs 1; P = .012), and more outpatient CF exacerbations requiring treatment (1.5 vs 0; P = .023) per year than patients without depression. CONCLUSION: Identified risk factors may be used to increase depression screening of CF pediatric patients, allowing for early detection and screening in this potentially high-risk patient population. More studies are needed to determine efficacious treatment for depression in pediatric CF patients.

CFTR Modulators for the Treatment of Cystic Fibrosis.

Defects in a single gene lead to the defective proteins that cause cystic fibrosis, making the disease an ideal candidate for mutation-targeted therapy. Although ivacaftor is currently the only FDA-approved CFTR modifier, others are in development.

Elexacaftor/Tezacaftor/Ivacaftor use in Pediatric Cystic Fibrosis Patients with Advanced Liver Disease.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy extends the life expectancy of people with cystic fibrosis (PwCF). However, CFTR modulators have not been well studied in patients with cystic fibrosis liver disease (CFLD), specifically those with advanced liver disease with portal hypertension. The purpose of this report is to describe the use of elexacaftor/tezacaftor/ivacaftor (ETI) in pediatric CF patients with advanced CFLD. METHODS: This retrospective case series included PwCF < 18 years old with baseline advanced CFLD initiated on ETI. RESULTS: Eleven PwCF and advanced CFLD were treated with ETI; six started a reduced dose regimen. No patient required treatment interruption and four patients received dose changes related to increase in transaminase and/or bilirubin elevations. Mean (SD) change in ppFEV1 from prior to ETI to highest value during therapy was 14.27 % (4.25) (p = 0.007). When evaluating the group as whole, AST decreased from baseline to last reported -15.18 (23.23) units/L (p = 0.054) and ALT slightly increased 0.73 (39.13) units/L (p = 0.96). Bilirubin increased minimally overall for patients with mean change from baseline of 0.83 (1.33) mg/dL [range -0.5-3] (p = 0.17). A model for time on ETI showed a significant decrease in AST over time of 0.955 per month of ETI but no other liver biochemistries were significant. No patient experienced decompensation of CFLD. CONCLUSION: ETI therapy in pediatric CF patients with advanced CFLD can be beneficial in improving pulmonary and nutritional outcomes without negative impact on liver biochemistries or hepatic outcomes. Close monitoring is recommended to ensure safety and tolerability.

Educational Initiative to Increase Knowledge for Transition to Adult Care in Adolescents With Cystic Fibrosis.

OBJECTIVE: Preparation for transition from pediatric to adult cystic fibrosis (CF) care is essential for successful self-management in adulthood. The primary objective of this study was to determine if education improved performance on follow-up assessments to increase knowledge for transition into adult care. The secondary objective of this study was to identify areas of greatest educational opportunity for adolescent CF patients. METHODS: A knowledge assessment containing 13 multiple-choice questions was given to patients between 14 and 19 years of age. Three educational handouts covering topics including nutrition, pancreatic enzyme replacement therapy, or vitamins were provided when a question corresponding to the topic was answered incorrectly. The same assessment was completed at the next clinic appointment as a follow-up. The scores of initial and follow-up assessments were compared based on number of correct answers. Additionally, the number of educational handouts provided was analyzed to determine area of greatest educational need. RESULTS: The average score ± SD on the initial assessment was 8.3 ± 1.6 of 13 questions answered correctly. For patients who completed both assessments, scores improved significantly between initial and follow-up assessments (8.4 ± 1.8 before education vs 10.3 ± 1.1 after; p = 0.0008). Nutrition, pancreatic enzyme, and vitamin handouts were given to 14 (70%), 17 (85%), and 20 (100%) patients, respectively. CONCLUSIONS: This pharmacist-driven educational initiative increased knowledge assessment scores after education was provided. Future studies of similar knowledge assessments starting at younger ages and other disease topics may determine if targeted education is the optimal way to build knowledge for transition to adult CF care.

Evaluation of the safety of piperacillin-tazobactam extended infusion in pediatric cystic fibrosis patients.

BACKGROUND: Patients with cystic fibrosis (CF) may be treated with piperacillin-tazobactam (PZT) for acute pulmonary exacerbations. Extending the infusion of PZT is one strategy to increase efficacy. Direct comparison, with respect to the incidence of acute kidney injury (AKI), between these two strategies has not been evaluated in pediatric patients with CF. The primary objective of this study was to compare the incidence of AKI in pediatric CF patients receiving extended infusion (EI) PZT versus traditional infusion (TI). METHODS: This IRB-approved, retrospective analysis included patients ages 30 days to 18 years that received PZT for at least 48 h between January 1, 2008, and January 1, 2020. PZT was infused over 30 min (TI group) or 4 h (EI group). RESULTS: Two hundred and four patients were included (TI: 109, EI: 95). Median age was 8 years (4-13) and 7 years (3-12) in the TI and EI groups (p = 0.15). The groups did not differ significantly in their baseline characteristics. There were 12 (11%) AKIs in the TI group and 8 (8.4%) in the EI group (p = 0.53). There was one occurrence of serum sickness in the TI group and none in the EI group. The incidence of thrombocytopenia was similar between the two groups. Median treatment duration was 8 days (5-11) and 9 days (5-13) for the TI and EI groups, respectively (p = 0.24). CONCLUSIONS: There was no significant increase in AKI in pediatric patients with CF receiving PZT by EI compared with TI. EI may be utilized to optimize the pharmacokinetics of PZT in pediatric CF patients.

Cystic fibrosis transmembrane conductance regulator-modifying medications: the future of cystic fibrosis treatment.

OBJECTIVE: To review and evaluate cystic fibrosis transmembrane conductance regulator (CFTR) modulators for the treatment of cystic fibrosis (CF). DATA SOURCES: Literature was accessed through MEDLINE (1977-January 2012), the Cochrane Library, and International Pharmaceutical Abstracts (1977-March 2012). Search terms included ivacaftor, VX-770, VX-809, ataluren, PTC 124, CFTR modulator, and cystic fibrosis. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were evaluated for inclusion. Clinical trials and relevant review articles were evaluated for each CFTR modulator. DATA SYNTHESIS: CF is caused by a mutation in the gene that encodes for the CFTR protein; mutations can be separated into 5 different classes. Ivacaftor is a new CFTR potentiator that helps the CFTR channel open properly in patients with the CFTR mutation, G551D. Patients in one study had significant decreases in sweat chloride values and increases in pulmonary function tests. Ivacaftor was approved by the Food and Drug Administration (FDA) to be taken orally at a dose of 150 mg twice a day in G551D CF patients older than 6 years. Additional studies are investigating the use of ivacaftor in other gating mutations and in younger patients. VX-809 is a CFTR corrector that modulates the folding and trafficking of CFTR. VX-809 was originally studied alone in patients with F508del mutation but is now being used in combination with ivacaftor in Phase 2 studies. Ataluren allows the read through of premature stop codons, and studies in patients with CF with nonsense mutations show an increase in chloride transportation. Ataluren requires 3 times a day dosing and is currently in a Phase 3 placebo-controlled study. CONCLUSIONS: Three new agents, ivacaftor, VX-809, and ataluren, target the basic defects in CFTR production. Ivacaftor was recently FDA approved, while the other 2 agents are still in clinical trials. Patients with CF will benefit from personalized medicine based on their specific genotype.

Cost analysis before and after implementation of a computerized physician order entry order form for enoxaparin.

OBJECTIVE: The authors sought to analyze the impact of a computerized physician order entry (CPOE) order form for enoxaparin sodium injection (Lovenox) to reduce the daily cost of drug therapy by switching appropriate patients to once-daily enoxaparin administration. METHODS: The study population included patients older than 18 years of age who had been treated with enoxaparin from September 1 to December 31, 2008 (the pre-order form implementation group) and from March 1 to June 30, 2009 (the post-order form implementation group). The wholesale acquisition cost was used to determine the cost of enoxaparin per day. Appropriate dosing was established by chart review. RESULTS: The post-implementation group showed a trend toward a higher cost of enoxaparin therapy per day compared with the pre-implementation group (P = 0.23). There was a non-significant increase in appropriate dosing after implementation of the order form-from 64.5% before implementation to 71.5% after implementation (P = 0.13). In the overall cohort, although the authors controlled for other factors that could influence cost, patients who received the appropriate dose per protocol were 3.2 times more likely (95% confidence interval, 1.8-5.9; P = 0.001) to have lower enoxaparin drug costs per day of therapy. CONCLUSION: The use of a CPOE enoxaparin order form did not reduce the daily cost of therapy.

Evaluation of the safety of cefepime prolonged infusions in pediatric patients with cystic fibrosis.

OBJECTIVE: Pediatric cystic fibrosis (CF) patients possess unique pharmacokinetics and may benefit from prolonged beta-lactam infusions to optimize pharmacodynamics. This study compared adverse drug event (ADE) rates with cefepime prolonged (PI) and standard infusions (SI). METHODS: This retrospective study included pediatric patients treated with cefepime for CF exacerbations between 2009 and 2019. One encounter per patient was analyzed with prioritization of SI encounters given sample size limitations. Baseline lab abnormalities, seizure disorders, and bleeding were exclusion criteria. The primary outcome was a composite safety endpoint (acute kidney injury [AKI], hepatotoxicity, hematologic toxicity, neurotoxicity, and hypersensitivity). RESULTS: Of 188 patients, 135 received PI and 53 received SI. Baseline characteristics were similar between groups. More PI patients used CF transmembrane conductance regulator (CFTR) modulators (25% vs. 0%, p < 0.01) or had antibiotic allergies (62% vs. 38%, p = 0.02). Difference in rates of composite safety endpoint was not statistically significant between PI and SI (21 [15.6%] vs. 6 [11.3%] p = 0.46) nor was incidence of AKI (16 [11.8%] vs. 6 [11.3%], p = 0.92). Other ADEs were rarely observed. Length of stay (12.2 vs. 10.1 days, p = 0.06), change in discharge ppFEV1 from admission (13 vs. 12, p = 0.91) or from baseline (-4 vs. -6.5, p = 0.33), and time to next exacerbation (249.7 vs. 192.5 days, p = 0.93) were similar. CONCLUSIONS: No difference in risk of ADEs including AKI was seen with cefepime PI in pediatric CF patients. Clinical outcomes were not significantly different between groups, but sample size may have limited comparison. PI cefepime may be considered in pediatric CF patients to optimize pharmacodynamics.

Airway-rehydrating agents for the treatment of cystic fibrosis: past, present, and future.

OBJECTIVE: To review and evaluate airway-rehydrating agents used for the treatment of cystic fibrosis (CF). DATA SOURCES: Literature was retrieved through MEDLINE (1977-August 2010), Cochrane Library, and International Pharmaceutical Abstracts (1977-August 2010). Search terms used included hypertonic saline, inhaled mannitol, denufosol, Moli1901, lancovutide, and cystic fibrosis. Reference citations from selected articles were reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles published in English identified from the data sources were evaluated for inclusion. Clinical trials in humans and relevant review articles were evaluated for each airway-rehydrating agent. DATA SYNTHESIS: Use of airway-rehydrating agents for the treatment of CF is an expanding area. Hypertonic saline (7% NaCl) is currently the only commercially available airway-rehydrating agent recommended for chronic therapy in patients with CF and is being evaluated in younger patients. Inhaled mannitol is an investigational dry-powder inhalation agent that improves mucus clearance in a similar manner to hypertonic saline and produced a statistically significant increase in forced expiratory volume in 1 second in a Phase 3 trial. Denufosol, a P2Y(2) agonist, rehydrates the airway surface liquid bypassing the basic CF transmembrane conductance regulator (CFTR) protein defect. It produces improvement in pulmonary function and is being further evaluated in a Phase 3 trial. Lancovutide (Moli1901) is an investigational agent in early-phase trials that activates a calcium-dependent chloride channel, allowing chloride to enter the airway. CONCLUSIONS: Hypertonic saline is the primary airway-rehydrating agent used in the treatment of CF. Inhaled mannitol may become an alternative to hypertonic saline since it is faster and easier to administer. It remains unclear whether denufosol and lancovutide will be synergistic or antagonistic with hypertonic saline. Both agents have a unique mechanism of action that bypasses the basic CFTR defect.

Continuous-infusion antipseudomonal Beta-lactam therapy in patients with cystic fibrosis.

OBJECTIVE: We sought to evaluate the pharmacokinetics, efficacy, safety, stability, pharmacoeconomics, and quality-of-life effects of continuous-infusion antipseudomonal beta-lactam therapy in patients with cystic fibrosis (CF). DATA SOURCES: Literature retrieval was accessed through Medline (from 1950 to December 2010) using the following terms: cystic fibrosis; beta-lactams or piperacillin or ticarcillin or cefepime or ceftazidime or doripenem or meropenem or imipenem/cilastin or aztreonam; continuous infusion or constant infusion; drug stability; economics, pharmaceutical; and quality of life. In addition, reference citations from identified publications were reviewed. STUDY SELECTION AND DATA EXTRACTION: We evaluated all articles in English identified from the data sources. DATA SYNTHESIS: Patients with CF often harbor colonies of multidrug-resistant organisms, increasing the risk of suboptimal dosing and failure to meet the time above the minimum inhibitory concentration (T > MIC) pharmacodynamic targets. The pharmacokinetics of continuous-infusion antipseudomonal beta-lactam therapy in CF maintains serum concentrations above the MIC of susceptible strains and is more likely than intermittent infusion to achieve optimal T > MIC targets for some intermediate and resistant strains of Pseudomonas aeruginosa. Three noncomparative and four comparative studies have assessed the efficacy and safety of continuous-infusion antipseudomonal beta-lactam therapy during CF pulmonary exacerbations. Ceftazidime, the most extensively studied antibiotic for continuous infusion in CF, has been shown to improve forced expiratory volume in 1 second (FEV(1)), to improve forced vital capacity (FVC), and to extend the time between pulmonary exacerbations. Continuous-infusion cefepime has been studied in a small number of patients, and a trend toward improved pulmonary function has been observed. Continuous-infusion antipseudomonal beta-lactam therapy appears to be well tolerated, although most of the data pertain to ceftazidime. Because continuous infusion may necessitate that patients wear a portable pump in close proximity to the body, the stability of the antibiotic at body temperature must be considered. Several beta-lactams have good stability at body temperature (piperacillin/tazobactam, ticarcillin/clavulanate, and aztreonam) or acceptable if the medication cartridge is changed twice daily (cefepime and doripenem), whereas other beta-lactams have acceptable 24-hour stability only at lower temperatures (cefepime, ceftazidime, doripenem, and meropenem). Although no pharmacoeconomic studies have evaluated the cost-benefit of continuous infusion versus intermittent infusion in patients with CF, the potential medication cost reduction appears to be considerable. There is little information regarding the impact of continuous infusion on quality of life in patients with CF. CONCLUSION: Efficacy and safety studies suggest that ceftazidime, administered as a continuous infusion for the treatment of CF pulmonary exacerbations, is safe and effective; has the potential to reduce the costs of treatment; and is preferred to intermittent infusion among patients treated at home. Continuous-infusion ceftazidime may therefore be an alternative to traditional dosing on a case-by-case basis, such as for patients with multidrug-resistant isolates of P. aeruginosa. Treatment with continuous-infusion ceftazidime at home may be considered in such a case, assuming resources and support equivalent to the hospital setting can be ensured. Additional studies assessing the safety and efficacy of other antipseudomonal beta-lactams, when administered as a continuous infusion, during CF pulmonary exacerbations are needed.

Impact of a pharmacy technician and pharmacist on time to inhaled tobramycin therapy in a pediatric cystic fibrosis clinic.

BACKGROUND: Cystic fibrosis (CF) patients who grow Pseudomonas aeruginosa on respiratory culture are commonly prescribed inhaled tobramycin (TIS) to eradicate the organism. The objective of this study was to determine the impact of a pharmacy technician/pharmacist team, in conjunction with an integrated health-system specialty pharmacy (IHSSP), on the time from positive culture to prescribing and access to TIS in a pediatric CF clinic. METHODS: A retrospective study of CF patients positive for P. aeruginosa who were prescribed TIS for eradication. RESULTS: The study included 20 patients in the pregroup and 42 patients in the postgroup. Total median (interquartile range) days from positive culture to TIS being shipped to the patient from the pharmacy was significantly different: 15 (10.25-21) days in the pregroup and 9 (7-14) days in the post groups (p = .005). The time from positive culture to TIS prescribing was significantly different: 6 (5-12.75) days in the pregroup and 5 (3.75-6) days in the postgroup (p = .01). In the postgroup median time from prescription to the patient receiving the TIS was significantly different between the two groups 2 (2-5) days IHSSP group versus 6 (3-9) external specialty pharmacy group (p = .003). Time from prescription to prior authorization approval was the same in both groups. CONCLUSIONS: The addition of the pharmacy team reduced time from culture to TIS being received by the patient. Patients able to fill at the IHSSP received their medication sooner than an external specialty pharmacy. The study shows the benefit of an integrated pharmacy model in conjunction with an IHSSP.

A clinician survey of use assessment, documentation, and education about cannabis in persons with cystic fibrosis.

INTRODUCTION: To help open the clinician dialogue regarding cannabis use in persons with cystic fibrosis (CF) in the United States, we aimed to describe current practices of use assessment and documentation processes related to cannabis. METHODS: A cross-sectional, anonymous survey study was distributed via email to CF directors and coordinators and to the Cystic Fibrosis Foundation (CFF) listservs of nurse, pharmacist, dietitian, social worker, and psychology care team members. The survey tool included multiple choice, scaled, and open-ended items, which assessed participants' awareness of current cannabis laws in their state, prescribing practices for medical marijuana, screening and documentation practices, knowledge of and what indications participants believe cannabis and cannabidiol (CBD) could be beneficial. Data were analyzed using descriptive statistics. RESULTS: There were 282 survey participants, with majority as providers (28%) and social workers (29%), representing all US regions. Participants varied in terms of frequency of evaluating cannabis use, with 15.4% "always," 48.4% "sometimes," and 41% "rarely," or "never" asking about it. Regarding recreational versus medical cannabis use, 55.4% and 62.5% reported documentation of each type in the medical record, respectively. Participants reported appetite, pain, and nausea as the top three advocated indications for use. About 35% and 72% of participants felt "slightly" or "not at all" prepared to answer patient/family questions about cannabis and CBD, respectively. CONCLUSIONS: The approach to cannabis use assessment, documentation, and education across CF care centers is variable. There is a need for care team and patient/caregiver education materials about cannabis/CBD and CF.

Effects of CFTR modulators on pharmacokinetics of tobramycin during acute pulmonary exacerbations in the pediatric cystic fibrosis population.

BACKGROUND: Individuals with cystic fibrosis (CF) require higher dosages of aminoglycosides due to an increased volume of distribution (Vd ) and clearance. Optimal dosing of aminoglycosides in the CF population is essential as repeated exposure to aminoglycosides during acute pulmonary exacerbations increases risk of nephrotoxicity and ototoxicity. To date, no studies have evaluated whether chronic cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy affects pharmacokinetics of aminoglycoside antibiotics in patients with CF. The objective of this study was to determine if the addition of a CFTR modulator affects elimination rate (Ke ) for intravenously administered tobramycin in the pediatric CF population. METHODS: This retrospective study included patients aged 2 to 18 years with CF receiving chronic therapy with a CFTR modulator. Patients included had an admission both pre- and post-chronic CFTR modulator therapy during which they received therapy with IV tobramycin. RESULTS: Thirty-four patients were included in the study. The median time between pre- and post-modulator admissions was 16.5 (13.8) months. Duration of CFTR modulator therapy before post-modulator admission was a median of 8 (10.3) months. There was no significant difference in Ke (hr-1 ) between pre- and post-modulator therapy, 0.41 (0.21) pre and 0.39 (0.09) post (P = .5). Vd and peak concentration were similar between both groups. There was no difference in nephrotoxicity as defined by the pRIFLE criteria (P = .25). CONCLUSIONS: The pharmacokinetic parameters of intravenously administered tobramycin during admission for acute pulmonary exacerbation do not appear to change significantly after initiating chronic therapy with a CFTR modulator. Empiric dose adjustments for patients on CFTR modulators are not recommended.

Pharmacokinetic considerations in pediatric pharmacotherapy.

PURPOSE: The changes in physiological functions as children grow and organ systems mature result in pharmacokinetic alterations throughout childhood. These alterations in children result in absorption, distribution, metabolism, and excretion of drugs that are different from those seen in the typical adult diseased population. SUMMARY: Changes in gastrointestinal motility and gastric pH in neonates and infants affect the absorption rate and bioavailability of drugs. Skin absorption rate and extent can be altered by different skin structures and perfusion in young children. Intramuscular and rectal absorption become less predictable in children due to erratic absorption site perfusion and other factors. Children's body compositions also differ greatly from that in adults. Water-soluble drugs distribute more extensively in newborns due to larger water content than in older children and adults. Drug elimination and excretion are also affected in pediatric population due to differences in liver and renal function. Immature enzyme development and renal function result in reduced clearance of drugs in young children. There are limited pharmacokinetic data available for many drugs used in children. CONCLUSION: Considering the changes in pharmacokinetics in children can help pharmacists optimize the dosing and monitoring of drugs and do the best they can to help this vulnerable population.

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.

Piperacillin-tazobactam versus cefepime incidence of acute kidney injury in combination with vancomycin and tobramycin in pediatric cystic fibrosis patients.

BACKGROUND: Cystic fibrosis (CF) patients often receive prolonged courses of broad spectrum antibiotics, such as piperacillin-tazobactam or cefepime in combination with vancomycin and tobramycin. The objective of this study was to determine the difference in AKI for pediatric CF patients receiving piperacillin-tazobactam or cefepime in combination with vancomycin and tobramycin. METHODS: IRB approval from a single CF center was obtained for this retrospective cohort study. Charts were evaluated from December 1, 2008 to June 30,2015. Patients were included if they had a diagnosis of CF, age 30 days to 18 years, and received intravenous vancomycin, tobramycin, and piperacillin-tazobactam or cefepime. The primary outcome was difference of AKI incidence in patients receiving piperacillin-tazobactam or cefepime, as defined by modified pediatric risk, injury, failure, loss, end stage renal disease (pRIFLE) criteria. RESULTS: Seventy-one patients were included with a median (interquartile range) age 11 years (7-16) and weight 36.2 kg (22.7-50). AKI was identified in 54.5% (18/33) of patients receiving piperacillin-tazobactam and 13.2% (5/38) of patients receiving cefepime (P ≤ 0.0001). One patient receiving piperacillin-tazobactam experienced acute renal failure. There was a slight difference in length of admission (13 vs 10 days, P = 0.042), but no difference in days to maximum SCr (6 vs 3, P = 0.127) nor FEV1 percent predicted on admission (69% vs 65%, P = 1.00). CONCLUSIONS: AKI occurred in nearly 55% of patients with piperacillin-tazobactam therapy versus 13% of patients with cefepime therapy, which suggests cefepime may be preferred in combination with vancomycin and tobramycin for pediatric CF patients.