Personalized Dosing of Medicines for Children: A Primer on Pediatric Pharmacometrics for Clinicians.

The widespread use of drugs for unapproved purposes remains common in children, primarily attributable to practical, ethical, and financial constraints associated with pediatric drug research. Pharmacometrics, the scientific discipline that involves the application of mathematical models to understand and quantify drug effects, holds promise in advancing pediatric pharmacotherapy by expediting drug development, extending applications, and personalizing dosing. In this review, we delineate the principles of pharmacometrics, and explore its clinical applications and prospects. The fundamental aspect of any pharmacometric analysis lies in the selection of appropriate methods for quantifying pharmacokinetics and pharmacodynamics. Population pharmacokinetic modeling is a data-driven method ('top-down' approach) to approximate population-level pharmacokinetic parameters, while identifying factors contributing to inter-individual variability. Model-informed precision dosing is increasingly used to leverage population pharmacokinetic models and patient data, to formulate individualized dosing recommendations. Physiologically based pharmacokinetic models integrate physicochemical drug properties with biological parameters ('bottom-up approach'), and is particularly valuable in situations with limited clinical data, such as early drug development, assessing drug-drug interactions, or adapting dosing for patients with specific comorbidities. The effective implementation of these complex models hinges on strong collaboration between clinicians and pharmacometricians, given the pivotal role of data availability. Promising advancements aimed at improving data availability encompass innovative techniques such as opportunistic sampling, minimally invasive sampling approaches, microdialysis, and in vitro investigations. Additionally, ongoing research efforts to enhance measurement instruments for evaluating pharmacodynamics responses, including biomarkers and clinical scoring systems, are expected to significantly bolster our capacity to understand drug effects in children.

Antimicrobial Stewardship in Pediatric Emergency Medicine: A Narrative Exploration of Antibiotic Overprescribing, Stewardship Interventions, and Performance Metrics.

Antibiotic overprescribing is prevalent in pediatric emergency medicine, influenced by clinician-caregiver dynamics and diagnostic uncertainties, and poses substantial risks such as increasing antibacterial resistance, adverse drug reactions, and increased healthcare expenditures. While antimicrobial stewardship programs have proven effective in optimizing antibiotic use within inpatient healthcare settings, their implementation in pediatric emergency medicine presents specific challenges. Existing biomarkers like white blood cell count, C-reactive protein, procalcitonin, and presepsin have limitations in their ability to distinguish (serious) bacterial infections from other etiologies of fever. Furthermore, rapid antigen detection tests and guidelines aimed at guiding antibiotic prescriptions for children have not consistently reduced unnecessary antibiotic use. To improve antibiotic prescribing practices, potential strategies include the utilization of decision support tools, audit and feedback, establishing follow-up procedures, implementing safety netting systems, and delivering comprehensive training and supervision. Notably, host genome signatures have also gained attention for their potential to facilitate rapid and precise diagnoses of inflammatory syndromes. Standardized metrics are crucial for evaluating antimicrobial use within pediatric healthcare settings, enabling the establishment of benchmarks for assessing antibiotic utilization, quality enhancement initiatives, and research endeavors.

Trends in Antibiotic Use in a Large Children's Hospital in London (United Kingdom): 5 Years of Point Prevalence Surveys.

Background: Antibiotics are commonly prescribed in paediatrics. As their excessive use contributes to adverse drug events, increased healthcare costs, and antimicrobial resistance, antimicrobial stewardship initiatives are essential to optimising medical care. These single-centre point prevalence surveys aimed to provide insights into antibiotic prescribing trends and identify targets for paediatric AMS activities. Methods: 14 point prevalence surveys were conducted from March 2016-April 2021, collecting data on antibiotic prescriptions, indication, adherence to guidelines, and route of administration. The UK adapted the World Health Organisation's AWaRe classification-guided antibiotic categorization. Results: 32.5% of all inpatients were on at least one antimicrobial; this remained stable during all surveys (range: 20-44%, p = 0.448). Of all prescriptions, 67.2% had an end- or review-date, and the majority was for agents in the Watch category (46.8-70.5%). Amoxicillin and clavulanate were the most frequently prescribed antibiotics (20.8%), followed by gentamicin (15.3%). Approximately 28.8% of all prescriptions were for prophylactic indications, while 7.6% of the prescriptions were not adherent to the hospital guidelines. Conclusions: This study highlights the importance of ongoing monitoring and robust AMS initiatives to ensure prudent antibiotic prescribing in paediatric healthcare. It underscores the need for tailored guidelines, educational efforts, and targeted interventions to enhance the quality of antibiotic usage, ultimately benefiting both individual patients and public health.

Clinical criteria for Mucosal Leishmaniasis diagnosis in rural South America: A systematic literature review.

BACKGROUND: Mucosal Leishmaniasis (ML), a neglected tropical disease caused by Leishmania parasites, impairs the quality of life of under-resourced populations in South America. If not treated promptly, this disease progresses to facial deformities and death. The low sensitivity of microscopy results and the unavailability of other accurate tests hamper the diagnosis. As clinical criteria are readily available in any setting, these may be combined in a syndromic algorithm, which in turn can be used as a diagnostic tool. We explore potential clinical criteria for a syndromic diagnostic algorithm for ML in rural healthcare settings in South America. METHODOLOGY/PRINCIPAL FINDINGS: The protocol for this systematic review was pre-registered in PROSPERO with the number: CRD42017074148. In patients with ML, described in case series identified through a systematic retrieval process, we explored the cumulative ML detection rates of clinical criteria. Participants: all patients with active mucosal disease from an endemic area in South America. Any original, non-treatment study was eligible, and case reports were excluded. PUBMED, EMBASE, Web of Science, SCIELO, and LILACS databases were searched without restrictions. The risk of bias was assessed with the JBI checklist for case series. We included 10 full texts describing 192 ML patients. Male gender had the highest detection rate (88%), followed by ulcer of the nasal mucosa (77%), age >15 (69%), and symptom duration >4 months (63%). SIGNIFICANCE: Within this selection of patients, we found that the male gender, ulcer of the nasal mucosa, age >15, and symptom duration >4 months lead to the highest detection rates. However, higher detection comes -naturally- with a higher rate of false positives as well. As we only included ML patients, this could not be verified. Therefore, the criteria that we found to be most promising should be validated in a well-designed prospective study.

Pharmacokinetics of Antimicrobials in Children with Emphasis on Challenges Faced by Low and Middle Income Countries, a Clinical Review.

Effective antimicrobial exposure is essential to treat infections and prevent antimicrobial resistance, both being major public health problems in low and middle income countries (LMIC). Delivery of drug concentrations to the target site is governed by dose and pharmacokinetic processes (absorption, distribution, metabolism and excretion). However, specific data on the pharmacokinetics of antimicrobials in children living in LMIC settings are scarce. Additionally, there are significant logistical constraints to therapeutic drug monitoring that further emphasize the importance of understanding pharmacokinetics and dosing in LMIC. Both malnutrition and diarrheal disease reduce the extent of enteral absorption. Multiple antiretrovirals and antimycobacterial agents, commonly used by children in low resource settings, have potential interactions with other antimicrobials. Hypoalbuminemia, which may be the result of malnutrition, nephrotic syndrome or liver failure, increases the unbound concentrations of protein bound drugs that may therefore be eliminated faster. Kidney function develops rapidly during the first years of life and different inflammatory processes commonly augment renal clearance in febrile children, potentially resulting in subtherapeutic drug concentrations if doses are not adapted. Using a narrative review approach, we outline the effects of growth, maturation and comorbidities on maturational and disease specific effects on pharmacokinetics in children in LMIC.

Hypocalcemia as a Cause of Complex Febrile Seizures in a Toddler.

A 13-month-old boy had suffered three episodes of complex febrile seizures. At this admission, there were signs of hyperexcitability, such as Trousseau sign and QTc prolongation. A point of care blood gas analysis revealed severe hypocalcemia. Therefore, prior to administering intravenous calcium gluconate, we took blood samples to investigate the etiology of this hypocalcemia: magnesium, parathormone, and 25-hydroxyvitamin D. Since both parathormone and phosphate were significantly elevated and 25-hydroxyvitamin D was within the normal range, pseudohypoparathyroidism was diagnosed. After two years of follow-up, serum calcium had normalized in our patient under supplementation of vitamin D and calcium. He had been free of convulsions, although different febrile episodes had occurred.

Physiologically-Based Pharmacokinetic model for Ciprofloxacin in children with complicated Urinary Tract Infection.

In a recent multicenter population pharmacokinetic study of ciprofloxacin administered to children suffering from complicated urinary tract infection (cUTI), the apparent volume of distribution (V) and total plasma clearance (CL) were decreased by 83.6% and 41.5% respectively, compared to healthy children. To understand these differences, a physiologically-based pharmacokinetic model (PBPK) for ciprofloxacin was developed for cUTI children. First, a PBPK model in adults was developed, modified incorporating age-dependent functions and evaluated with paediatric data generated from a published model in healthy children. Then, the model was then adapted to a cUTI paediatric population according to the degree of renal impairment (KF) affecting renal clearance (CLRenal,) and CYP1A2 clearance (CLCYP1A2). Serum and urine samples obtained from 22 cUTI children were used for model evaluation. Lastly, a parameter sensitivity analysis identified the most influential parameters on V and CL. The PBPK model predicted the ciprofloxacin exposure in adults and children, capturing age-related pharmacokinetic changes. Plasma concentrations and fraction excreted unchanged in urine (fe) predictions improved in paediatric cUTI patients once CLrenal and CLCYP1A2 were corrected by KF. The presented PBPK model for ciprofloxacin demonstrates its adequacy to simulate different dosing scenarios to obtain PK predictions in a healthy population from 3 months old onwards. Model adaptation of CLRenal and CLCYP1A2 according to KF explained partially the differences seen in the plasma drug concentrations and fe vs time profiles between healthy and cUTI children. Nevertheless, it is necessary to further investigate the disease-related changes in cUTI to improve model predictions.

Results of a Multicenter Population Pharmacokinetic Study of Ciprofloxacin in Children with Complicated Urinary Tract Infection.

Resistance rates for ciprofloxacin, which is labeled for treating complicated urinary tract infections in children, are rapidly rising. As there is limited knowledge on developmental pharmacology of ciprofloxacin, the primary aim of this study was to develop a population pharmacokinetic model for ciprofloxacin in children treated for complicated urinary tract infections. Children to whom ciprofloxacin was prescribed, intravenous (10 to 15 mg/kg body weight every 12 h) or per os (15 to 20 mg/kg every 12 h), were enrolled. One hundred eight serum and 119 urine samples were obtained during 10 intravenous and 13 oral courses of ciprofloxacin in 22 patients (age range, 0.31 to 15.51 years). A one-compartment model best described our data. Fat-free mass and glomerular filtration rate (estimated by a formula using cystatin C and creatinine), standardized for body surface area, were significant covariates for ciprofloxacin clearance. In our population, ciprofloxacin clearance is 0.16 to 0.43 liter/h/kg of body weight, volume of distribution 0.06 to 2.88 liters/kg, and bioavailability 59.6%. All of our patients had a clinical cure of their infection. Based on target attainment simulations across doses, all children reached the pharmacodynamic target for Enterobacteriaceae, but on average only 53% did for Pseudomonas aeruginosa and 3% for Staphylococcus aureus, at the 15-mg/kg oral dose. For treating urinary tract infections caused by Pseudomonas aeruginosa, oral doses should be at least 20 mg/kg. Furthermore, in our population, fat-free mass and kidney function should be considered, as they prove to be significant covariates for ciprofloxacin clearance and, hence, exposure. (This study has been registered at ClinicalTrials.gov under identifier NCT02598362.).

Ethical considerations of researchers conducting pediatric clinical drug trials: a qualitative survey in two Belgian university children's hospitals.

There is a general consensus about the underlying theoretical ethical principles that ground the practice of pediatric clinical trials: scientific necessity, good risk/benefit ratio, minimized burden, and parental consent/child assent. However, these principles are so broadly construed that it is not always clear how they should be applied in clinical practice. We conducted a qualitative study at Ghent University Hospital and the hospital of the Dutch-speaking university of Brussels on how researchers weigh ethical principles, assess the risk/benefit balance, estimate patient experience, and experience informed consent procedures in pediatric drug studies. Based on our assessment of the burden and risk versus benefit ratio in 62 pediatric drug research protocols, we selected 21 studies for further study to maximize diversity. Twenty-seven researchers (17 physicians, 10 study nurses) completed a qualitative survey about their study. We compared their responses to our assessments. The risk benefit assessment of our participants about their own research projects resembled our assessment almost perfectly. Assessing burden appeared to be more subjective. The researchers were confident in their ability to obtain valid consent. However, we question whether this confidence is warranted. CONCLUSION: We argue for constant ethical reflexivity in pediatric clinical trials, because broad ethical principles are not always easy to apply to specific situations. What is Known: • Several international guidelines and a large body of scientific literature indicate a broad consensus about the basic ethical framework for pediatric clinical trials, based on risk benefit assessment and respect for autonomy. • Little is known about how researchers implement these broad principles in practice. What is New: • Researchers' risk/benefit assessments about their own studies resembled the assessment of neutral peers, assessing burden was more subjective. • Researchers were very confident in their ability to obtain valid informed consent.

Systemic fluoroquinolone prescriptions for hospitalized children in Belgium, results of a multicenter retrospective drug utilization study.

BACKGROUND: Fluoroquinolones (FQ) are increasingly prescribed for children, despite being labeled for only a limited number of labeled pediatric indications. In this multicenter retrospective drug utilization study, we analyzed indications for systemic FQ prescriptions in hospitalized children and the appropriateness of the prescribed dose. METHODS: Using data obtained from electronic medical files, the study included all children who received a systemic FQ prescription in two Belgian university children's hospitals between 2010 and 2013. Two authors reviewed prescribed daily doses. Univariate and multivariate logistic regression models were used to analyze risk factors for inadequately dosing. Results262 FQ prescriptions for individual patients were included for analysis. 16.8% of these prescriptions were for labeled indications, and 35.1% were guided by bacteriological findings. Prescribed daily dose was considered to be inappropriate in 79 prescriptions (30.2%). Other FQ than ciprofloxacin accounted for 9 prescriptions (3.4%), of which 8 were correctly dosed. Underdosing represented 45 (56.9%) dosing errors. Infants and preschool children were at particular risk for dosing errors, with associated adjusted OR of 0.263 (0.097-0.701) and 0.254 (0.106-0.588) respectively. CONCLUSIONS: FQ were often prescribed off-label and not guided by bacteriological findings in our study population. Dosing errors were common, particularly in infants and preschool children. FQ prescriptions for children should be improved by specific pediatric antimicrobial stewardship teams. Furthermore, pharmacokinetic studies should optimise dosing recommendations for children.