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Objective: To assess whether beta-lactam extended or continuous beta-lactam infusions (EI/CI) improve clinical outcomes in children with proven or suspected bacterial infections., Study Design: We included observational and interventional studies that compared beta-lactam EI or CI with standard infusions in children less than 18 years old, and reported on mortality, hospital or intensive care unit length of stay, microbiological cure, and/or clinical cure. Data sources included PubMed, Medline, EBM Reviews, EMBASE, and CINAHL and were searched from January 1, 1980, to November 3, 2023. Thirteen studies (2945 patients) were included: 5 randomized control trials and 8 observational studies. Indications for antimicrobial therapies and clinical severity varied, ranging from cystic fibrosis exacerbation to critically ill children with bacteriemia., Results: EI and CI were not associated with a reduction in mortality in randomized control trials (n = 1464; RR 0.93, 95% CI 0.71, 1.21), but were in observational studies (n = 833; RR 0.43, 95% CI 0.19, 0.96). We found no difference in hospital length of stay. Results for clinical and microbiological cures were heterogeneous and reported as narrative review. The included studies were highly heterogeneous, limiting the strength of our findings. The lack of shared definitions for clinical and microbiological cure outcomes precluded analysis., Conclusions: EI and CI were not consistently associated with reduced mortality or length of stay in children. Results were conflicting regarding clinical and microbiological cures. More well-designed studies targeting high-risk populations are necessary to determine the efficacy of these alternative dosing strategies., Competing Interests: Declaration of Competing Interest Amélie Marsot receives salary subsidy as chercheur boursier Junior 1 from the Fonds de Recherche Québec Santé (FRQS). Nadia Roumeliotis receives funding support as a clinician scientist from the Fonds de Recherche Québec Santé (FRQS) and the Canadian Institute for Health Research (CIHR) for projects unrelated to this work. The other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Guidelines for vancomycin therapeutic monitoring recommend using a Bayesian approach with a population pharmacokinetic model to estimate the 24 h area under the concentration-time curve over first-order equations. Thus, we performed an external evaluation of population pharmacokinetic models of vancomycin in neonates and compared Bayesian results with those observed in clinical practice via pharmacokinetic equations to improve therapeutic monitoring by proposing optimized initial dosing nomograms and assessing the feasibility of reduced blood sampling strategies using the most predictive models., Methods: Models were identified from the literature and evaluated via an external neonatal population. A priori predictive performance was first assessed by prediction-based diagnostics, then by simulation-based diagnostics and a posteriori analyses only if deemed satisfactory; model-informed vancomycin exposure was also compared with reference first-order pharmacokinetic equations. The best-performing models were ultimately subjected to Monte Carlo simulations to develop new initial dosing nomograms offering the highest probability of achieving therapeutic target., Results: A total of 28 population pharmacokinetic models were evaluated in the external dataset, which includes 72 neonates and 380 vancomycin concentrations. Eleven models had an adequate predictive performance with bias ≤ ± 15% and imprecision ≤ $$ \le $$ 30%, while the Bayesian approach yielded over 75% agreement with reference exposure values in most cases. Nonetheless, Capparelli et al. and Mehrotra et al. models performed the best overall, showing the lowest imprecisions of 16.8% and 16.9%, respectively; both models recommended higher dosage regimens than the theoretical nomogram currently applied to favor therapeutic target attainment., Discussion: We externally evaluated numerous neonatal population pharmacokinetic models of vancomycin and used the most predictive ones to advocate new initial dosing nomograms. Clinical implementation of the Bayesian approach could reduce the time needed to reach therapeutic target and limit the number of blood samples in newborns compared with traditional pharmacokinetic equations., (© 2024 The Author(s). Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy published by Wiley Periodicals LLC on behalf of Pharmacotherapy Publications, Inc.)

Background: An increase in Staphylococcus aureus infections has been reported in pediatric patients with cystic fibrosis (CF) over the last few years. This pathogen is commonly treated with vancomycin, an antibiotic for which therapeutic drug monitoring (TDM) is recommended. Updated guidelines were recently published regarding new targets of exposure for the TDM of vancomycin through a Bayesian approach, using population pharmacokinetic (popPK) models., Objectives: This study aims to assess the predictive performance of vancomycin popPK models in pediatric patients with CF and to recommend optimal initial dosing regimens based on simulations., Methods: Patient data were collected from two centers in Canada, and a literature review was conducted to identify all published vancomycin popPK models for pediatric CF patients. External evaluation and simulations were performed according to patient and occasion of treatment., Results: A total of 53 vancomycin concentrations were collected from six pediatric CF patients. Only two popPK models of vancomycin for pediatric CF patients were identified through the literature review. The external evaluation results for both centers combined revealed a population bias of 28.1% and an imprecision of 33.7%. A re-estimation of parameters was performed to improve predictive performance. The optimal initial dosing regimen was 15 mg/kg/dose administered every 6 hours according to the per occasion remodel., Conclusion: The predictive performance and identified optimal initial dosing regimens associated with the model were different depending on the data used, showing external evaluation's importance before implementing a model in clinical practice., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Vancomycin therapeutic monitoring guidelines were revised in March 2020, and a population pharmacokinetics-guided Bayesian approach to estimate the 24-hour area under the concentration-time curve to the minimum inhibitory concentration ratio has since been recommended instead of trough concentrations. To comply with these latest guidelines, we evaluated published population pharmacokinetic models of vancomycin using an external dataset of neonatal patients and selected the most predictive model to develop a new initial dosing regimen., Methods: The models were identified from the literature and tested using a retrospective dataset of Canadian neonates. Their predictive performance was assessed using prediction- and simulation-based diagnostics. Monte Carlo simulations were performed to develop the initial dosing regimen with the highest probability of therapeutic target attainment., Results: A total of 144 vancomycin concentrations were derived from 63 neonates in the external population. Five of the 28 models retained for evaluation were found predictive with a bias of 15% and an imprecision of 30%. Overall, the Grimsley and Thomson model performed best, with a bias of -0.8% and an imprecision of 20.9%; therefore, it was applied in the simulations. A novel initial dosing regimen of 15 mg/kg, followed by 11 mg/kg every 8 hours should favor therapeutic target attainment., Conclusions: A predictive population pharmacokinetic model of vancomycin was identified after an external evaluation and used to recommend a novel initial dosing regimen. The implementation of these model-based tools may guide physicians in selecting the most appropriate initial vancomycin dose, leading to improved clinical outcomes., Competing Interests: Conflicts of interest statement: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II trial (NCT03363217). Preliminary data shows potential benefits with significant response in the majority of PLGG and PN and an overall good tolerance. Moreover, possible benefits of MEK inhibitor therapy on cognitive functioning in neurofibromatosis type 1 (NF1) were recently shown which supports the need for further evaluation., Methods: Thirty-six patients with NF1 (age range 3-19 years) enrolled in the phase II study of trametinib underwent a neurocognitive assessment at inclusion and at completion of the 72-week treatment. Age-appropriate Wechsler Intelligence Scales and the Trail Making Test (for children over 8 years old) were administered at each assessment. Paired t-tests and Reliable Change Index (RCI) analyses were performed to investigate change in neurocognitive outcomes. Regression analyses were used to investigate the contribution of age and baseline score in the prediction of change., Results: Stable performance on neurocognitive tests was revealed at a group-level using paired t-tests. Clinically significant improvements were however found on specific indexes of the Wechsler intelligence scales and Trail Making Test, using RCI analyses. No significant impact of age on cognitive change was evidenced. However, lower initial cognitive performance was associated with increased odds of presenting clinically significant improvements on neurocognitive outcomes., Conclusion: These preliminary results show a potential positive effect of trametinib on cognition in patients with NF1. We observed significant improvements in processing speed, visuo-motor and verbal abilities. This study demonstrates the importance of including neuropsychological evaluations into clinical trial when using MEK inhibitors for patients with NF1., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Asthma is one of the most prevalent chronic diseases of childhood and disproportionately affects children with lower socioeconomic status. Controller medications such as inhaled corticosteroids significantly reduce asthma exacerbations and improve symptoms. However, a large proportion of children still have poor asthma control, in part owing to suboptimal adherence. Financial barriers contribute to hindering adherence, as do behavioral factors related to low income. For example, unmet social needs for food, lodging, and childcare may create stress and worry in parents, negatively influencing medication adherence. These needs are also cognitively taxing and force families to focus on immediate needs, leading to scarcity and heightening future discounting; thus, there is the tendency to attribute greater value to the present than to the future in making decisions., Objective: In this project, we will investigate the relationship between unmet social needs, scarcity, and future discounting as well as their predictive power over time on medication adherence in children with asthma., Methods: This 12-month prospective observational cohort study will recruit 200 families of children aged 2 to 17 years at the Asthma Clinic of the Centre Hospitalier Universitaire Sainte-Justine, a tertiary care pediatric hospital in Montreal, Canada. The primary outcome will be adherence to controller medication, measured using the proportion of prescribed days covered during follow-up. Exploratory outcomes will include health care use. The main independent variables will be unmet social needs, scarcity, and future discounting, measured using validated instruments. These variables will be measured at recruitment as well as at 6- and 12-month follow-ups. Covariates will include sociodemographics, disease and treatment characteristics, and parental stress. Primary analysis will compare adherence to controller medication, measured using the proportion of prescribed days covered, between families with versus those without unmet social needs during the study period using multivariate linear regression., Results: The research activities of this study began in December 2021. Participant enrollment and data collection began in August 2022 and are expected to continue until September 2024., Conclusions: This project will allow the documentation of the impact of unmet social needs, scarcity, and future discounting on adherence in children with asthma using robust metrics of adherence and validated measures of scarcity and future discounting. If the relationship between unmet social needs, behavioral factors, and adherence is supported by our findings, this will suggest the potential for novel targets for integrated social care interventions to improve adherence to controller medication and reduce risk across the life course for vulnerable children with asthma., Trial Registration: ClinicalTrials.gov NCT05278000; https://clinicaltrials.gov/ct2/show/NCT05278000., International Registered Report Identifier (irrid): PRR1-10.2196/37318., (©Olivier Drouin, Tamara Perez, Tracie A Barnett, Francine M Ducharme, Eric Fleegler, Arvin Garg, Kim Lavoie, Patricia Li, Marie-Élaine Métras, Serge Sultan, Sze Man Tse, Jiaying Zhao. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 07.03.2023.)

Despite ongoing international efforts, many drugs administered to children must be compounded from dosage forms designed for adults because they remain unavailable in commercial formulations that suit their needs. Even though oral drug compounding is common in pediatrics, the extent of this practice has not been well described in recent years. This cross-sectional and retrospective study was conducted at a Canadian university-affiliated, 484-bed, tertiary care pediatric hospital and its rehabilitation centre on two randomly selected days. A total of 606 hospitalized children with 5465 prescriptions were included. Overall, compounded drugs for enteral administration (CDEA) represented 13% of all prescriptions (enteral and parenteral) and 23% of prescriptions for enteral administration. Of the 390 prescribed drugs, 122 required compounding. CDEA were mostly liquids (n = 478 [67%]) and mainly included drugs of the central nervous (35%), cardiovascular (21%), and gastro-intestinal (12%) systems. Nearly half (N = 298 [49%]) of children had at least one CDEA prescribed in their medical file. Many CDEA are available as commercial products in other jurisdictions. Collaboration is needed between all stakeholders to make these drugs available to Canadian children.

Objectives: Non-adherence to anti-infective therapy contributes to treatment failure and the emergence of bacterial resistance. This study aimed to assess at-home adherence, by paediatric patients, to oral anti-infective (OAI) therapy prescribed for treatment of acute infections and to explore the factors contributing to non-adherence., Methods: This prospective descriptive study involved French-speaking patients under 16 years of age who were discharged with one or more OAIs prescribed for home administration for a maximum of 30 days. Telephone surveys were used to assess overall adherence, which consisted of primary adherence (patient's ability to procure the medication) and secondary adherence (patient's ability to take the treatment as prescribed)., Results: Overall, 51.7% (30/58) of patients were adherent to OAI therapy, with 100% primary adherence (n=69/69) and 51.7% secondary adherence (n=30/58). On average, patients took 98% of the total number of doses prescribed, and non-adherence was related mostly to not following medication administration schedules (63.3% of patients followed the exact schedule). Indeed, the adherence rate for patients taking one or two doses per day was twice the rate for patients taking more than two doses per day (81.8% vs 44.7%, p=0.043)., Conclusions: Half of the paediatric patients treated for acute infections were non-adherent to OAI therapy at home. Interventions are needed to improve this situation., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To evaluate clinicians' and patients' perceptions of pharmacogenetic testing in a clinical setting. Materials & methods: This is a pragmatic mixed-method prospective observational study. Hospital pharmacists and neurologists participated in focus groups regarding pharmacogenetic testing; patients who received pharmacogenetic testing and their community pharmacists completed surveys to assess their perception of these tests. Results: Most study participants had a positive view of pharmacogenetic testing. Three major themes were identified from the focus groups: receptiveness to pharmacogenetic testing, pharmacogenetic test characteristics and integrating pharmacogenetic tests into practice. Conclusion: The views reported are encouraging for the eventual implementation of pharmacogenetics in practice. Local integration of these tests is an essential step to improve patient care through personalized medicine.

Background: The pharmacist's role within the multidisciplinary team is often poorly understood. Various interventions can be put into place to promote the role of the pharmacist in the hospital setting with families, patients, and other health care professionals. Few studies have described the feasibility and assessed the impact of such interventions, particularly in pediatrics., Objectives: To describe the implementation of a 3-part intervention aimed at increasing the visibility of pharmacists and their role on the treatment team, with the goal of optimizing the pharmaceutical care of hospitalized patients in the general pediatric units of CHU Sainte-Justine, in Montréal, Quebec, and to compare the perceptions and satisfaction of patients' parents and of health care professionals with exposure to either usual pharmaceutical care or to pharmaceutical care incorporating the intervention., Methods: This single-blind, randomized, controlled experimental study involved patients admitted to general pediatric units between March 5 and August 8, 2019. In addition to usual care, the intervention included delivery of an information brochure about pharmaceutical services and care, access to a telephone line (which allowed families and patients to contact a pharmacy resident during their stay in hospital and up to 1 month after discharge), and completion of a standardized discharge form by the pharmacist responsible for the patient. The participants and health professionals concerned were surveyed to determine their perceptions and level of satisfaction., Results: A total of 641 participants were included in the study, 321 in the intervention group and 320 in the control group. The brochure was given to all parents in the intervention group. Twelve phone calls were made through the dedicated telephone line. The standardized discharge form was completed for 46.7% (150/321) of the participants in the intervention group. Most of the parents and patients who responded to the survey, in either group (81.2%, 298/367), reported satisfaction with the pharmaceutical services and care received. Of participants in the intervention group, 83.9% were satisfied with the pharmaceutical care and services received, compared with 78.5% of those in the control group (p = 0.18). In addition, 60.3% (111/184) of participants in the intervention group said that the information about medications that was provided during the hospital stay gave them new knowledge, compared with 48.1% (87/181) of those in the control group (p = 0.019). The results of the survey showed that care providers were in agreement with the intervention., Conclusions: The 3 components of the intervention were implemented in the pediatric units over a period of 5 months. The intervention was perceived as positive by the parents and care providers concerned, and the respondents were mostly satisfied with the services and pharmaceutical care offered., Competing Interests: Conflits d’intérêts: Aucune déclaration., (2021 Canadian Society of Hospital Pharmacists. All content in the Canadian Journal of Hospital Pharmacy is copyrighted by the Canadian Society of Hospital Pharmacy. In submitting their manuscripts, the authors transfer, assign, and otherwise convey all copyright ownership to CSHP.)

Introduction: Pharmacogenetics represents an opportunity in pharmaceutical practice. There are many documentary resources to support the pharmacist's work in this area., Objective: To compare the recommendations for carrying out pharmacogenetic tests from a documentary source in three countries: the United States, Canada and United France., Method: This is a cross-sectional descriptive study. Based on the recommendations of the Clinical Pharmacogenetics Implementation Consortium type A (the highest threshold justifying the use of a pharmacogenetic test), we identified the drug-gene pairs (23 pairs). The proposed pairs involve a total of 47 separate international nonproprietary names and 18 genes. For each drug-gene pair, we consulted three open access documentary sources (one for each target country), namely the pharmaceutical products database (DPD) for Canada, the product characteristic summary (SPC) for France and the Micromedex® monograph (IBM, Truven Health Analytics, MI, USA) for the United States. The study was conducted in September 2019., Results: About a third of the drug-gene pairs are explicitly mentioned by the gene to be targeted and by the test suggested in the documentary sources consulted. Of the 23 pairs identified by the CPIC, thirteen pairs contain "consistent" recommendations between the three documentary sources., Conclusion: There is great heterogeneity regarding the recommendations for pharmacogenetic tests from three documentary sources used by pharmacists to monitor drug therapy in the United States, Canada and France. There is an urgent need to standardize the requirements for nomenclature, description and the need to use pharmacogenetic tests to ensure proper use of drugs and these tests in the clinic., (Copyright © 2020 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Background: Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofibromas (PNs) which are low-grade tumors involving peripheral nerves in patients with neurofibromatosis type 1 (NF1). These lesions are known to be refractory to chemotherapy. Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma. We have observed significant responses to trametinib in patients with refractory PLGG in our institutions and results from the phase I study are promising. The treatment appears not only efficacious but is also usually well tolerated. We hypothesize that we will observe responses in the majority of refractory PLGG and PN treated with trametinib in this phase 2 study., Methods: The primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups. Group 1 includes NF1 patients with progressing/refractory glioma. Group 2 includes NF1 patients with plexiform neurofibroma. Group 3 includes patients with progressing/refractory glioma with KIAA1549-BRAF fusion. Group 4 includes other patients with progressing/refractory glioma with activation of the MAPK/ERK pathway. Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, overall survival, safety and tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment., Discussion: Trametinib will allow us to target directly and specifically the MAPK/ERK pathway. We expect to observe a significant response in most patients. Following our study, trametinib could be integrated into standard treatment of PLGG and PN., Trial Registration: ClinicalTrials.gov Identifier: NCT03363217 December 6, 2017.

Objective: To describe the problems faced by young patients and their parents when obtaining and using compounded drugs., Methods: This prospective observational descriptive study included patients 0 to 21 years of age who were discharged from a mother-child tertiary hospital with a prescription containing at least one compounded drug between February 2016 and July 2016. Families were called 7 to 10 business days after discharge to complete a telephone follow-up questionnaire. Retail pharmacies were contacted to obtain additional information in order to compare the dispensed compounded drug with the prescription and published master formulas., Results: The parents of 71 patients with a median age of 6.9 months were surveyed regarding 99 compounded drugs corresponding to 34 different oral formulations. Out of 314 issues identified, 252 were considered as problems: 9 involved major and 243 minor problems with real or potential consequences., Conclusion: This study identified a significant number of compounding-related problems. It suggests that current practice standards are insufficient and action should be taken to improve the use and the dispensation of compounded drugs to ensure patients' safety.