Impact of a Pediatric Emergency Medicine Pharmacist, Institutional Guideline, and Electronic Order Set on Empiric Antimicrobial Use for Febrile Neutropenia.

OBJECTIVES: This study evaluated the difference in appropriateness of antimicrobial selection in pediatric patients with febrile neutropenia (FN) after implementation of an institutional guideline, a dedicated pediatric emergency medicine (EM) pharmacist, and an electronic order set. METHODS: This was a retrospective cohort study that included febrile patients aged younger than 18 years who were at risk of neutropenia, as defined by our institutional algorithm. Charts were evaluated for inclusion by searching for patients who presented to the emergency department (ED) between February 2018 and January 2022 who had International Classification of Diseases, Tenth Revision (ICD-10) codes for patients at risk of FN. Three independent groups were compared before, during, and after interventions. A historical control group (group 1), postdedicated EM pharmacist and institutional guideline cohort (group 2), and postdedicated EM pharmacist, institutional guideline, and electronic order set cohort (group 3) were compared. Secondary outcomes included time from registration in the ED to administration of the first dose of empiric antimicrobials, days to defervescence, pediatric intensive care unit length of stay, and hospital length of stay. RESULTS: Seventy-eight charts were reviewed for inclusion. Among those included (n = 38), there was an increase in appropriate use of antimicrobials from 71% to 92% to 100% ( P = 0.1534) between group 1, group 2, and group 3, respectively. In addition, the interventions in this study lead to an overall decrease in the median time from registration to first dose of antibiotics from 142 minutes to 72 minutes ( P = 0.1370). CONCLUSIONS: This study demonstrated the positive impact a pediatric EM pharmacist along with an institutional guideline and an electronic order set have on appropriate antimicrobial selection in pediatric FN patients. Institutions should consider multipronged approaches to improve the selection and time to administration of appropriate empiric antimicrobials in the ED.

Description of Bivalirudin Use for Anticoagulation in Pediatric Patients on Mechanical Circulatory Support.

BACKGROUND: Although heparin has previously been the anticoagulant of choice during mechanical circulatory support (MCS), there is a lack of consistency in dose-response in pediatric patients. Bivalirudin offers more consistent dose-response in adults; however, there are limited data for pediatrics use. OBJECTIVE: The purpose was to characterize the usage, dosage, and safety profile of bivalirudin when used for pediatric MCS in a tertiary care pediatric hospital. METHODS: A retrospective review of pediatric patients receiving bivalirudin for extracorporeal membrane oxygenation/ventricular assist device (ECMO/VAD) anticoagulation was conducted. The primary outcome was the average dose of bivalirudin. Additional outcomes included initial and maximum bivalirudin dose, time to first therapeutic activated partial thromboplastin time (aPTT), time within goal aPTT range, bleeding and clotting complications, and cost. Data were compared between ECMO and VAD patients. RESULTS: Thirty-four patients were included. The median dose of bivalirudin was 0.37 mg/kg/h (interquartile range [IQR] = 0.21-0.56), with a maximum dose of 0.62 mg/kg/h (IQR = 0.33-0.91). VAD patients had a higher median and maximum dose as compared with ECMO patients. Patients achieved their therapeutic goal in a median of 6.1 hours and averaged 61.9% time within therapeutic aPTT. One patient had significant hemorrhage, whereas 3 patients had clotting requiring a circuit change. Bivalirudin acquisition cost was higher than heparin. CONCLUSION AND RELEVANCE: Bivalirudin dosing in ECMO and VAD patients is consistent with dosing seen in previous reports but may be higher in VAD patients. Comparative studies between heparin and bivalirudin are necessary to compare cost-effective outcomes for pediatric patients.

An Evaluation of Risperidone Dosing for Pediatric Delirium in Children Less Than or Equal to 2 Years of Age.

Background: Risperidone dosing and safety data are limited in patients ≤2 years of age. Objective: To describe the dosing strategies, safety, and tolerability of risperidone in infants ≤2 years of age. Methods: An institutional review board-approved retrospective study was conducted in a 24-bed pediatric intensive care unit at an academic medical center in patients ≤2 years of age receiving risperidone for the management of ICU delirium. The primary outcome was mean initial daily dose of risperidone. Secondary outcomes included mean daily dose, dosing frequency, treatment duration, and adverse effects. Results: Seventeen patients who received at least 1 dose of risperidone were included in the study. The initial daily dose ranged from 0.1 to 0.25 mg (0.01-0.04 mg/kg), with a mean of 0.17 mg (0.02 mg/kg). Most patients were initiated on once-daily dosing (76.5%) versus twice-daily dosing (17.6%). More than 80% of patients required a dose increase during therapy. Median daily doses of fentanyl, morphine, ketamine, and midazolam were decreased following initiation of risperidone. No adverse events that led to discontinuation of risperidone were reported. Conclusion and Relevance: Risperidone was found to be safe and well tolerated at daily doses of risperidone of 0.1 to 0.25 mg in 1 or 2 doses per day in patients ≤2 years old for the management of ICU delirium. To our knowledge, these results provide the largest cohort describing dosing recommendations specific for risperidone in this age group. Further investigation on the effect of antipsychotic administration on other sedation and analgesic regimens is necessary.

Factors contributing to variability of glycan microarray binding profiles.

Protein-carbohydrate interactions play significant roles in a wide variety of biological systems. Glycan microarrays are commonly utilized to interrogate the selectivity, sensitivity, and breadth of these complex protein-carbohydrate interactions. During the past two decades, numerous distinct glycan microarray platforms have been developed, each assembled from a variety of slide-surface chemistries, glycan-attachment chemistries, glycan presentations, linkers, and glycan densities. Comparative analyses of glycan microarray data have shown that while many protein-carbohydrate interactions behave predictably across microarrays, there are instances when various array formats produce different results. For optimal construction and use of this technology, it is important to understand sources of variances across array platforms. In this study, we performed a systematic comparison of microarray data from 8 lectins across a range of concentrations on the CFG and neoglycoprotein array platforms. While there was good general agreement on the binding specificity of the lectins on the two arrays, there were some cases of large discrepancies. Differences in glycan density and linker composition contributed significantly to variability. The results provide insights for interpreting microarray data and designing future glycan microarrays.

Female low dose tip syringes-increased complexity of use may compromise dosing accuracy in paediatric patients.

WHAT IS KNOWN AND OBJECTIVE: The International Organization for Standardization (ISO) created enteral device specifications to reduce tubing misconnections. The Global Enteral Device Supplier Association (GEDSA) supports a female design: standard and low dose tip (LDT). Concerns include increased complexity of use with adapters, dosing accuracy and workflow. No peer-reviewed studies have evaluated dosing accuracy of the complete female system with adapters. The objective of this study was to compare dosing accuracy of the female design to legacy syringes. METHODS: An in vitro study was conducted at the University of Florida College of Pharmacy pharmaceutics laboratory. Assessments were completed for syringe size, dispense methods and volumes, and adapters when applicable. A gravimetric scale and specific gravity were used to calculate administration volumes. The primary outcome was frequency administration volume exceeded 10% expected amount. RESULTS AND DISCUSSION: A total of 576 tests were performed. The LDT resulted in significantly higher rates of unacceptable dosing variance compared to legacy (21.2% vs 7.4%, P = 0.003). Variance exceeding 10% occurred more frequently with LDT 0.5 and 1 mL syringes, medication cup dispensing (liquid or tablet) and inappropriate LDT adapter use. Unapproved adapter processes compared to FDA-approved processes held a higher likelihood of unacceptable dosing variance (28% vs 7.4%, P < 0.001). FDA-approved use of adapters with prefilled syringes compared to bedside administration may result in higher rates of dosing inaccuracy (18.8% vs 5.6%, P = 0.06). WHAT IS NEW AND CONCLUSIONS: This study raises clinical concerns of dosing inaccuracies with the LDT syringes, particularly with 0.5 and 1 mL sizes. The use of adapters significantly increases the opportunity for inaccurate dosing.

Humoral response to a viral glycan correlates with survival on PROSTVAC-VF.

Therapeutic cancer vaccines can be effective for treating patients, but clinical responses vary considerably from patient to patient. Early indicators of a favorable response are crucial for making individualized treatment decisions and advancing vaccine design, but no validated biomarkers are currently available. In this study, we used glycan microarrays to profile antiglycan antibody responses induced by PROSTVAC-VF, a poxvirus-based cancer vaccine currently in phase III clinical trials. Although the vaccine is designed to induce T-cell responses to prostate-specific antigen, we demonstrate that this vaccine also induces humoral responses to a carbohydrate on the poxvirus, the Forssman disaccharide (GalNAcα1-3GalNAcß). These responses had a statistically significant correlation with overall survival in two independent sample sets (P = 0.015 and 0.008) comprising more than 100 patients. Additionally, anti-Forssman humoral responses correlated with clinical outcome in a separate study of PROSTVAC-VF combined with a radiopharmaceutical (Quadramet). Studies on control subjects demonstrated that the survival correlation was specific to the vaccine. The results provide evidence that antiglycan antibody responses may serve as early biomarkers of a favorable response to PROSTVAC-VF and offer unique insights for improving vaccine design.

New Inhaled Antimicrobial Formulations for Use in the Cystic Fibrosis Patient Population.

OBJECTIVE: To review the current literature on inhaled antibiotic therapies currently in clinical trials for cystic fibrosis (CF) patients. DATA SOURCES: A literature search was performed using PubMed (1975 to September 2015), International Pharmaceutical Abstracts (1970 to September 2015), and MEDLINE (1946 to September 2015) to identify studies for inclusion. The following search terms were used: cystic fibrosis, inhaled amikacin, inhaled liposomal amikacin, inhaled vancomycin, and/or inhaled levofloxacin. STUDY SELECTION AND DATA EXTRACTION: All English-language phase II to III studies evaluating efficacy and/or safety, case reports, and retrospective studies of inhaled amikacin, inhaled vancomycin, and inhaled levofloxacin in CF patients were included. DATA SYNTHESIS: Currently available inhaled antibiotics, tobramycin and aztreonam, have demonstrated improvement in respiratory function of CF patients. Newer agents have shown potentially similar efficacy, with improvement in ease of use. Limited data suggest that inhaled liposomal amikacin and levofloxacin are both noninferior to tobramycin in terms of improvements in respiratory function. Inhaled levofloxacin has a lower rate of hospitalizations secondary to respiratory exacerbations and a reduction in the Pseudomonas aeruginosa sputum density compared with inhaled tobramycin. Inhaled vancomycin use has been documented in case reports and 2 small retrospective eradication trials, although data are limited to support its use. CONCLUSIONS: The horizon of inhaled antibiotic choices for CF patients is promising. The introduction of different drug classes and formulations to treat resistant Gram-negative and Gram-positive organisms increases the number of options for patients for both eradication and treatment of chronic colonization.

Cross-platform comparison of glycan microarray formats.

Carbohydrates participate in almost every aspect of biology from protein sorting to modulating cell differentiation and cell-cell interactions. To date, the majority of data gathered on glycan expression has been obtained via analysis with either anti-glycan antibodies or lectins. A detailed understanding of the specificities of these reagents is critical to the analysis of carbohydrates in biological systems. Glycan microarrays are increasingly used to determine the binding specificity of glycan-binding proteins (GBPs). In this study, six different glycan microarray platforms with different modes of glycan presentation were compared using five well-known lectins; concanavalin A, Helix pomatia agglutinin, Maackia amurensis lectin I, Sambucus nigra agglutinin and wheat germ agglutinin. A new method (universal threshold) was developed to facilitate systematic comparisons across distinct array platforms. The strongest binders of each lectin were identified using the universal threshold across all platforms while identification of weaker binders was influenced by platform-specific factors including presentation of determinants, array composition and self-reported thresholding methods. This work compiles a rich dataset for comparative analysis of glycan array platforms and has important implications for the implementation of microarrays in the characterization of GBPs.

Mitochondrial transcription factor A regulates mitochondrial transcription initiation, DNA packaging, and genome copy number.

Mitochondrial transcription factor A (mtTFA, mtTF1, TFAM) is an essential protein that binds mitochondrial DNA (mtDNA) with and without sequence specificity to regulate both mitochondrial transcription initiation and mtDNA copy number. The abundance of mtDNA generally reflects TFAM protein levels; however, the precise mechanism(s) by which this occurs remains a matter of debate. Data suggest that the usage of mitochondrial promoters is regulated by TFAM dosage, allowing TFAM to affect both gene expression and RNA priming for first strand mtDNA replication. Additionally, TFAM has a non-specific DNA binding activity that is both cooperative and high affinity. TFAM can compact plasmid DNA in vitro, suggesting a structural role for the non-specific DNA binding activity in genome packaging. This review summarizes TFAM-mtDNA interactions and describes an emerging view of TFAM as a multipurpose coordinator of mtDNA transactions, with direct consequences for the maintenance of gene expression and genome copy number. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.

Strategies for Implementing Pediatric Dose Standardization: Considerations From the Vizient University Health System Consortium Pharmacy Network Pediatric Pharmacy Committee.

Pediatric patients are at a heightened risk for medication errors due to variability in medication ordering and administration. Dose rounding and standardization have been 2 practices historically used to reduce variability and improve medication safety. This article will describe strategies for implementing pediatric dose standardization. Local practice often dictates the operational decisions made at an institutional level, leading to a lack of a standard methodology. Vizient survey results demonstrate there is wide variation in dose standardization and ready-to-use (RTU) practices although most responding institutions have attempted to limit bedside manipulation to reduce medication error. There are many barriers to consider before pursuing dose standardization at an institution. These include selecting medications to standardize, calculating appropriate standardized doses, preparing RTU products, and supplying the products to the patient. Strategies to overcome implementation issues are described as well as identification of knowledge gaps related to the preparation and use of RTU products in the pediatric population. There is opportunity to enhance an institution's ability to provide RTU medications. Although there are several barriers, those that have had successful implementation have leveraged their information technology systems, garnered multidisciplinary support, and customized their practice to meet their operational demands.

Pharmacy student self-assessment of strength of residency candidacy compared to clinical faculty.

INTRODUCTION: The purpose of this study was to compare student and faculty perceptions of strength of residency candidacy and to identify student preferences and perceptions that influence the process of being selected by a residency program beyond standard application materials. METHODS: A 31-item questionnaire was administered to third-year and fourth-year pharmacy students to collect information regarding factors deemed important for successful residency program candidacy. Global assessment of strength of residency candidacy was self-rated by students and a group of clinical faculty blinded to student responses. Interrater reliability for student-to-faculty and faculty-to-faculty perceptions of strength of residency candidacy was determined. RESULTS: Students generally reported good academic metrics and participation in a wide variety of scholarly activities deemed important in attaining a residency position. Students rated overall strength of residency candidacy as "above average" (n = 54, 37.2%), "average" (n = 60, 41.4%), and "below average" (n = 31, 21.3%), and self-perception increased with matriculation. Student self-assessment of strength of residency candidacy compared to faculty assessment showed poor agreement (mean [SD] kappa = 0.27 [0.08]). Faculty concordance in assessment of strength of residency candidacy was moderate (α = 0.55). CONCLUSIONS: Concordance in self-assessment of strength of residency candidacy of students compared to faculty was poor. In contrast, agreement among faculty was moderate with generally lower ratings compared to student self-rating, suggesting that students are overconfident in this regard. These findings support residency preparedness training in pharmacy curricula which should include formal assessment of strength of residency candidacy to identify gaps.

A Review of Bivalirudin for Pediatric and Adult Mechanical Circulatory Support.

As the use of mechanical circulatory support has increased in volume and complexity, anticoagulation remains an intricate component of a patient's pharmacotherapy plan. Traditionally, heparin has been the primary anticoagulant utilized because of its ease of titration and  familiarity of use. More recently, bivalirudin, a direct thrombin inhibitor, has attracted attention as a potential alternative to traditional therapy. While labeled for use in percutaneous coronary interventions, it is utilized off-label for heparin-induced thrombocytopenia and mechanical circulatory support. A literature search identified ten studies in which bivalirudin was used in extracorporeal membrane oxygenation and five studies in which it was used in ventricular assist devices. The purpose of this review was to summarize the currently available literature for bivalirudin use for mechanical circulatory support in both adult and pediatric patients.

CSF neurofilament light may predict progression from amnestic mild cognitive impairment to Alzheimer's disease dementia.

Neurofilament light (NfL) is a promising biomarker of neurodegeneration in Alzheimer's disease (AD). In this study, cerebrospinal fluid (CSF) NfL was measured in a 24-month longitudinal cohort consisting of control (n = 52), amnestic mild cognitive impairment (aMCI) (n = 55), and probable AD dementia (n = 28) individuals. The cohort was reevaluated after 6-10 years. Baseline CSF NfL was significantly elevated in aMCI and probable AD dementia groups compared to controls (p < 0.0001). CSF NfL was significantly lower in stable aMCI patients compared to aMCI patients who converted to probable AD dementia within the 24-month period (p = 0.004). Substituting T-tau for NfL in the core AD biomarkers model (Aß42/P-tau/T-tau) did not improve ability to separate control and AD, or stable and converter aMCI patients. Our results support that elevated CSF NfL could predict progression in aMCI patients, but its utility cannot improve the core AD biomarkers.

Bivalirudin May Reduce the Need for Red Blood Cell Transfusion in Pediatric Cardiac Patients on Extracorporeal Membrane Oxygenation.

We retrospectively compared anticoagulation with heparin and bivalirudin for 32 consecutive children under 18 years old during extracorporeal membrane oxygenation (ECMO) in our pediatric cardiac intensive care unit (PCICU). Between September 2015 and January 2018, 14 patients received heparin, 13 venoarterial (VA), and 1 venovenous (VV). From February 2018 to September 2019, 18 received bivalirudin (all VA). The mean (standard deviation [SD]) percentage of time with therapeutic activated partial thromboplastin time and activated clotting time was bivalirudin 54 (14%) and heparin 57 (11%), p = 0.4647, and percentage of time supratherapeutic was bivalirudin 18 (10%) and heparin 27 (12%), p = 0.0238. Phlebotomy-associated blood loss per hour of ECMO was double in the heparin compared with bivalirudin group 1.08 ml/h (0.20 ml/h), compared with 0.51 ml/h (0.07 ml/h), p = 0.0003, as well as interventions to control bleeding. Packed red blood cell (PRBC) transfusions significantly correlated with higher blood loss in the heparin group (Pearson correlation coefficient = 0.49, p = 0.0047). Overall amount of blood product utilization was not different between the groups. Survival to ECMO decannulation was 89% for bivalirudin and 57% for heparin, p = 0.0396, although 6 month survival was not significantly different (67% versus 57%, p = 0.5809). Heparin may increase the need for PRBC transfusions and strategies to attenuate bleeding when compared with bivalirudin for children receiving ECMO in PCICU.

The Pharmacists' Role in Disease Outbreaks: Navigating the Dynamics of Uncertainty Before, During, and After Disease Outbreaks.

Vaccination rates are on the decline as parents avoid doctor's visits with their children. In addition, the antivaccination movement has led to a significant portion of the population remaining unvaccinated or undervaccinated. Outbreaks in the United States within the past year have highlighted the need for better education and communication regarding the efficacy and safety of vaccinations as well as important steps to reduce disease transmission. Patients may be fearful and have questions about how these outbreaks will affect themselves and their families, especially those in immunocompromised states and pregnant women. Pharmacists are poised to provide this education and start a dialogue with patients and other health care professionals with regard to disease outbreaks. Additionally, in times of outbreak, pharmacists encounter obscure questions from both healthy and at-risk populations that fear contraction of a particular disease. The purpose of this commentary is to describe previous outbreaks and to explore the pharmacists' role in disease prevention.

Inborn Errors of Metabolism in Pediatric Epilepsy.

Patients with refractory epilepsy from inborn errors of metabolism typically present as neonates. Direct supplementation with the deficient vitamin or cofactor is recommended, and case series report both efficacy and safety data of these agents. Some conditions may also occur together, necessitating multiple treatments. Despite effective and early treatment, patients are at heightened risk for neurological sequela. The literature on seizures related to metabolic deficiencies for pediatric patients is limited but has some guidance on appropriate dosing and monitoring for agents to target specific deficiencies, which may help with narrowing antiepileptic therapies, reducing side effects, and improving neurodevelopmental outcomes and quality of life. The focus of this review is to discuss the pharmacotherapy, including the most updated published efficacy and safety data, involved in treating refractory epilepsy as a result of metabolic errors.

An Updated Review of Clostridium difficile Treatment in Pediatrics.

Clostridium difficile infection (CDI) continues to have clinical and economic impact across all health care settings. Pediatrics accounts for a small percentage of worldwide infection; however, screening and diagnosis are confounded by asymptomatic colonization in young infants. Metronidazole and oral vancomycin have historically been the agents used to manage CDI in both pediatrics and adults. Newer agents and alternative therapies, such as fecal microbiota transplantation, may offer additional benefit. Recent guidelines updates from the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America separate pediatric and adult recommendations for epidemiology, diagnosis, and treatment. This review will discuss the risk factors, management, prevention, and updated guideline recommendations for CDI in the pediatric population.

A case of sinus pause induced by swallowing in the setting of olanzapine and guanfacine overdose.

Olanzapine, a second-generation antipsychotic, is used in both adult and pediatric populations for schizophrenia, bipolar disorder, and depression and has been associated with autonomic dysregulation in the setting of overdose. Guanfacine is a sympatholytic drug used in the treatment of attention deficit hyperactivity disorder and has also been associated with autonomic dysfunction. We present a unique case of a 17-year-old male who overdosed on 340 mg of olanzapine and 189 mg of extended-release guanfacine with a previously unreported adverse event. Specifically, five days after ingestion, he developed a 5-8 s sinus pause every time he forcefully swallowed any beverage, suggestive of a vagal hypersensitivity reaction. The report will review the autonomic dysfunction of olanzapine and guanfacine and management of asymptomatic sinus pause in the critical care setting.

Targeting glycosylation pathways and the cell cycle: sugar-dependent activity of butyrate-carbohydrate cancer prodrugs.

Short-chain fatty acid (SCFA)-carbohydrate hybrid molecules that target both histone deacetylation and glycosylation pathways to achieve sugar-dependent activity against cancer cells are described in this article. Specifically, n-butyrate esters of N-acetyl-D-mannosamine (But4ManNAc, 1) induced apoptosis, whereas corresponding N-acetyl-D-glucosamine (But4GlcNAc, 2), D-mannose (But5Man, 3), or glycerol (tributryin, 4) derivatives only provided transient cell cycle arrest. Western blots, reporter gene assays, and cell cycle analysis established that n-butyrate, when delivered to cells via any carbohydrate scaffold, functioned as a histone deacetylase inhibitor (HDACi), upregulated p21WAF1/Cip1 expression, and inhibited proliferation. However, only 1, a compound that primed sialic acid biosynthesis and modulated the expression of a different set of genes compared to 3, ultimately killed the cells. These results demonstrate that the biological activity of butyrate can be tuned by sugars to improve its anticancer properties.

Metabolic oligosaccharide engineering: perspectives, applications, and future directions.

Many adhesion and signaling molecules critical for development, as well as surface markers implicated in diseases ranging from cancer to influenza, contain oligosaccharides that modify their functions. Inside a cell, complex glycosylation pathways assemble these oligosaccharides and attach them to proteins and lipids as they traffic to the cell surface. Until recently, practical technologies to manipulate glycosylation have lagged unlike the molecular biologic and genetic methods available to intervene in nucleic acid and protein biochemistry; now, metabolic oligosaccharide engineering shows promise for manipulating glycosylation. In this methodology, exogenously-supplied non-natural sugars intercept biosynthetic pathways and exploit the remarkable ability of many of the enzymes involved in glycosylation to process metabolites with slightly altered chemical structures. To date, non-natural forms of sialic acid, GalNAc, GlcNAc, and fucose have been incorporated into glycoconjugates that appear on the cell surface; in addition O-GlcNAc protein modification involved in intracellular signaling has been tagged with modified forms of this sugar. Reactive functional groups, including ketones, azides, and thiols, have been incorporated into glycoconjugates and thereby provide chemical 'tags' that can be used for diverse purposes ranging from drug delivery to new modes of carbohydrate-based cell adhesion that can be used to control stem cell destiny. Finally, strategies for further engineering non-natural sugars to improve their pharmacological properties and provide complementary biological activities, such as addition of short chain fatty acids, are discussed in this article.