Prolonged Beta-lactam Infusions in Children: A Systematic Review and Meta-analysis.

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 LOS, 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 (2,945 patients) were included: 5 randomized control trials (RCTs), 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 RCTs (n = 1,464; 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 LOS 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.

Optimization of Vancomycin Initial Dosing Regimen in Neonates Using an Externally Evaluated Population Pharmacokinetic Model.

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.

Impact of trametinib on the neuropsychological profile of NF1 patients.

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.

Two months outcomes following delirium in the pediatric intensive care unit.

The lasting consequences of delirium in children are not well characterized. This study aimed to compare the two-month outcomes in pediatric intensive care unit (PICU) survivors according to the presence of delirium. Post-hoc analysis of a single-center prospective study of mechanically ventilated (invasive ventilation or non-invasive ventilation) children followed at the CHU Sainte-Justine PICU follow-up clinic two months after PICU discharge, between October 2018 and August 2022. Delirium was defined as one or more Cornell Assessment of Pediatric Delirium (CAPD) scores ≥ 9. Primary outcome was survivors' quality of life and secondary outcomes were sleep and posttraumatic stress and anxiety and depression in parents. Multivariable linear and logistic regression models assessed the independent associations between delirium and outcomes while adjusting for age, sex, comorbidity, diagnosis, severity of illness, PICU length of stay, and invasive mechanical ventilation. Of the 179 children included over a 47 month-period, 117 (65.4%) had delirium. Children with delirium were more commonly intubated (91.5% vs. 30.7%, p < 0.001) and had higher PELOD-2 scores (10 vs. 4, p < 0.001). On multivariable analysis, delirium was associated with a decreased quality of life at 2.3 months post discharge (p = 0.03). The severity of the delirium episode (higher scores of CAPD) was associated with a higher likelihood of sleep disturbances (OR 1.13, p = 0.01) and parental anxiety (OR 1.16, p = 0.01), in addition to lower quality of life (p = 0.03).Conclusions: Two months following their PICU stay, children with delirium had a lower quality of life, suggesting a lasting effect of delirium on children and their families.