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1.
Pediatr Nephrol ; 39(5): 1607-1616, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-37994980

RESUMEN

BACKGROUND: Augmented renal clearance (ARC) holds a risk of subtherapeutic drug concentrations. Knowledge of patient-, disease-, and therapy-related factors associated with ARC would allow predicting which patients would benefit from intensified dosing regimens. This study aimed to identify ARC predictors and to describe ARC time-course in critically ill children, using iohexol plasma clearance (CLiohexol) to measure glomerular filtration rate (GFR). METHODS: This is a retrospective analysis of data from the "IOHEXOL" study which validated GFR estimating formulas (eGFR) against CLiohexol. Critically ill children with normal serum creatinine were included, and CLiohexol was performed as soon as possible after pediatric intensive care unit (PICU) admission (CLiohexol1) and repeated (CLiohexol2) after 48-72 h whenever possible. ARC was defined as CLiohexol exceeding normal GFR for age plus two standard deviations. RESULTS: Eighty-five patients were included; 57% were postoperative patients. Median CLiohexol1 was 122 mL/min/1.73 m2 (IQR 75-152). Forty patients (47%) expressed ARC on CLiohexol1. Major surgery other than cardiac surgery and eGFR were found as independent predictors of ARC. An eGFR cut-off value of 99 mL/min/1.73 m2 and 140 mL/min/1.73 m2 was suggested to identify ARC in children under and above 2 years, respectively. ARC showed a tendency to persist on CLiohexol2. CONCLUSIONS: Our findings raise PICU clinician awareness about increased risk for ARC after major surgery and in patients with eGFR above age-specific thresholds. This knowledge enables identification of patients with an ARC risk profile who would potentially benefit from a dose increase at initiation of treatment to avoid underexposure. TRIAL REGISTRATION: ClinicalTrials.gov NCT05179564, registered retrospectively on January 5, 2022.


Asunto(s)
Enfermedad Crítica , Yohexol , Niño , Humanos , Creatinina , Enfermedad Crítica/terapia , Tasa de Filtración Glomerular , Pruebas de Función Renal , Estudios Retrospectivos
2.
Drug Metab Dispos ; 51(4): 499-508, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36639242

RESUMEN

Physiologically based pharmacokinetic (PBPK) models consist of compartments representing different tissues. As most models are only verified based on plasma concentrations, it is unclear how reliable associated tissue profiles are. This study aimed to assess the accuracy of PBPK-predicted beta-lactam antibiotic concentrations in different tissues and assess the impact of using effect site concentrations for evaluation of target attainment. Adipose, bone, and muscle concentrations of five beta-lactams (piperacillin, cefazolin, cefuroxime, ceftazidime, and meropenem) in healthy adults were collected from literature and compared with PBPK predictions. Model performance was evaluated with average fold errors (AFEs) and absolute AFEs (AAFEs) between predicted and observed concentrations. In total, 26 studies were included, 14 of which reported total tissue concentrations and 12 unbound interstitial fluid (uISF) concentrations. Concurrent plasma concentrations, used as baseline verification of the models, were fairly accurate (AFE: 1.14, AAFE: 1.50). Predicted total tissue concentrations were less accurate (AFE: 0.68, AAFE: 1.89). A slight trend for underprediction was observed but none of the studies had AFE or AAFE values outside threefold. Similarly, predictions of microdialysis-derived uISF concentrations were less accurate than plasma concentration predictions (AFE: 1.52, AAFE: 2.32). uISF concentrations tended to be overpredicted and two studies had AFEs and AAFEs outside threefold. Pharmacodynamic simulations in our case showed only a limited impact of using uISF concentrations instead of unbound plasma concentrations on target attainment rates. The results of this study illustrate the limitations of current PBPK models to predict tissue concentrations and the associated need for more accurate models. SIGNIFICANCE STATEMENT: Clinical inaccessibility of local effect site concentrations precipitates a need for predictive methods for the estimation of tissue concentrations. This is the first study in which the accuracy of PBPK-predicted tissue concentrations of beta-lactam antibiotics in humans were assessed. Predicted tissue concentrations were found to be less accurate than concurrent predicted plasma concentrations. When using PBPK models to predict tissue concentrations, this potential relative loss of accuracy should be acknowledged when clinical tissue concentrations are unavailable to verify predictions.


Asunto(s)
Modelos Biológicos , Monobactamas , Adulto , Humanos , Ceftazidima , Antibacterianos , Músculos
3.
Br J Clin Pharmacol ; 88(12): 4985-4996, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36256514

RESUMEN

Pharmacometric modelling plays a key role in both the design and analysis of regulatory trials in paediatric drug development. Studies in adults provide a rich source of data to inform the paediatric investigation plans, including knowledge on drug pharmacokinetics (PK), safety and efficacy. In children, drug disposition differs widely from birth to adolescence but extrapolating adult to paediatric PK, safety and efficacy either with pharmacometric or physiologically based approaches can help design or in some cases reduce the need for clinical studies. Aspects to consider when extrapolating PK include the maturation of drug metabolizing enzyme expression, glomerular filtration, drug excretory systems, and the expression and activity of specific transporters in conjunction with other drug properties such as fraction unbound. Knowledge of these can be used to develop extrapolation tools such as allometric scaling plus maturation functions or physiologically based PK. PK/pharmacodynamic approaches and well-designed clinical trials in children are of key importance in paediatric drug development. In this white paper, state-of-the-art of current methods used for paediatric extrapolation will be discussed. This paper is part of a conect4children implementation of innovative methodologies including pharmacometric and physiologically based PK modelling in clinical trial design/paediatric drug development through dissemination of expertise and expert advice. The suggestions arising from this white paper should define a minimum set of standards in paediatric modelling and contribute to the regulatory science.


Asunto(s)
Anticuerpos Monoclonales , Antineoplásicos Inmunológicos , Adolescente , Adulto , Niño , Humanos , Ensayos Clínicos como Asunto , Desarrollo de Medicamentos , Proyectos de Investigación
4.
Br J Clin Pharmacol ; 88(12): 4965-4984, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-34180088

RESUMEN

Developmental pharmacology describes the impact of maturation on drug disposition (pharmacokinetics, PK) and drug effects (pharmacodynamics, PD) throughout the paediatric age range. This paper, written by a multidisciplinary group of experts, summarizes current knowledge, and provides suggestions to pharmaceutical companies, regulatory agencies and academicians on how to incorporate the latest knowledge regarding developmental pharmacology and innovative techniques into neonatal and paediatric drug development. Biological aspects of drug absorption, distribution, metabolism and excretion throughout development are summarized. Although this area made enormous progress during the last two decades, remaining knowledge gaps were identified. Minimal risk and burden designs allow for optimally informative but minimally invasive PK sampling, while concomitant profiling of drug metabolites may provide additional insight in the unique PK behaviour in children. Furthermore, developmental PD needs to be considered during drug development, which is illustrated by disease- and/or target organ-specific examples. Identifying and testing PD targets and effects in special populations, and application of age- and/or population-specific assessment tools are discussed. Drug development plans also need to incorporate innovative techniques such as preclinical models to study therapeutic strategies, and shift from sequential enrolment of subgroups, to more rational designs. To stimulate appropriate research plans, illustrations of specific PK/PD-related as well as drug safety-related challenges during drug development are provided. The suggestions made in this joint paper of the Innovative Medicines Initiative conect4children Expert group on Developmental Pharmacology and the European Society for Developmental, Perinatal and Paediatric Pharmacology, should facilitate all those involved in drug development.


Asunto(s)
Modelos Biológicos , Farmacología , Humanos , Niño , Recién Nacido , Proyectos de Investigación , Recolección de Datos , Farmacocinética
5.
Eur J Pediatr ; 181(11): 3851-3866, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36053381

RESUMEN

Accurate renal function assessment is crucial to guide intensive care decision-making and drug dosing. Estimates of glomerular filtration rate (eGFR) are routinely used in critically ill children; however, these formulas were never evaluated against measured GFR (mGFR) in this population. We aimed to assess the reliability of common eGFR formulas compared to iohexol plasma clearance (CLiohexol) in a pediatric intensive care (PICU) population. Secondary outcomes were the prevalence of acute kidney injury (AKI) (by pRIFLE criteria) and augmented renal clearance (ARC) (defined as standard GFR for age + 2 standard deviations (SD)) within 48 h after admission based on mGFR and eGFR by the revised Schwartz formula and the difference between these two methods to diagnose AKI and ARC. In children, between 0 and 15 years of age, without chronic renal disease, GFR was measured by CLiohexol and estimated using 26 formulas based on creatinine (Scr), cystatine C (CysC), and betatrace protein (BTP), early after PICU admission. eGFR and mGFR results were compared for the entire study population and in subgroups according to age, using Bland-Altman analysis with calculation of bias, precision, and accuracy expressed as percentage of eGFR results within 30% (P30) and 10% (P10) of mGFR. CLiohexol was measured in 98 patients. Mean CLiohexol (± SD) was 115 ± 54 ml/min/1.73m2. Most eGFR formulas showed overestimation of mGFR with large bias and poor precision reflected by wide limits of agreement (LoA). Bias was larger with CysC- and BTP-based formulas compared to Scr-based formulas. In the entire study population, none of the eGFR formulas showed the minimal desired P30 > 75%. The widely used revised Schwartz formula overestimated mGFR with a high percentage bias of - 18 ± 51% (95% confidence interval (CI) - 29; - 9), poor precision with 95% LoA from - 120 to 84% and insufficient accuracy reflected by P30 of only 51% (95% CI 41; 61), and P10 of 21% (95% CI 13; 66) in the overall population. Although performance of Scr-based formulas was worst in children below 1 month of age, exclusion of neonates and younger children did not result in improved agreement and accuracy. Based on mGFR, prevalence of AKI and ARC within 48 h was 17% and 45% of patients, respectively. There was poor agreement between revised Schwartz formula and mGFR to diagnose AKI (kappa value of 0.342, p < 0.001; sensitivity of 30%, 95% CI 5; 20%) and ARC (kappa value of 0.342, p < 0.001; sensitivity of 70%, 95% CI 33; 58). CONCLUSION: In this proof-of-concept study, eGFR formulas were found to be largely inaccurate in the PICU population. Clinicians should therefore use these formulas with caution to guide drug dosing and therapeutic interventions in critically ill children. More research in subgroup populations is warranted to conclude on generalizability of these study findings. CLINICALTRIALS: gov NCT05179564, registered retrospectively on January 5, 2022. WHAT IS KNOWN: • Both acute kidney injury and augmented renal clearance may be present in PICU patients and warrant adaptation of therapy, including drug dosing. • Biomarker-based eGFR formulas are widely used for GFR assessment in critically ill children, although endogenous filtration biomarkers have important limitations in PICU patients and eGFR formulas have never been validated against measured GFR in this population. WHAT IS NEW: • eGFR formulas were found to be largely inaccurate in the PICU population when compared to measured GFR by iohexol clearance. Clinicians should therefore use these formulas with caution to guide drug dosing and therapeutic interventions in critically ill children. • Iohexol plasma clearance could be considered an alternative for accurate GFR assessment in PICU patients.


Asunto(s)
Lesión Renal Aguda , Insuficiencia Renal Crónica , Lesión Renal Aguda/diagnóstico , Adolescente , Biomarcadores , Niño , Preescolar , Creatinina , Enfermedad Crítica , Tasa de Filtración Glomerular , Humanos , Lactante , Recién Nacido , Yohexol , Reproducibilidad de los Resultados , Estudios Retrospectivos
6.
Pediatr Crit Care Med ; 23(7): e309-e318, 2022 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-35426861

RESUMEN

OBJECTIVES: In critically ill children, severely altered pharmacokinetics may result in subtherapeutic ß-lactam antibiotic concentrations when standard pediatric dosing regimens are applied. However, it remains unclear how to recognize patients most at risk for suboptimal exposure and their outcome. This study aimed to: 1) describe target attainment for ß-lactam antibiotics in critically ill children, 2) identify risk factors for suboptimal exposure, and 3) study the association between target nonattainment and clinical outcome. DESIGN: Post hoc analysis of the "Antibiotic Dosing in Pediatric Intensive Care" study (NCT02456974, 2012-2019). Steady-state trough plasma concentrations were classified as therapeutic if greater than or equal to the minimum inhibitory concentration of the (suspected) pathogen. Factors associated with subtherapeutic concentrations and clinical outcome were identified by logistic regression analysis. SETTING: The pediatric and cardiac surgery ICU of a Belgian tertiary-care hospital. PATIENTS: One hundred fifty-seven patients (aged 1 mo to 15 yr) treated intravenously with amoxicillin-clavulanic acid, piperacillin-tazobactam, or meropenem. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three hundred eighty-two trough concentrations were obtained from 157 patients (median age, 1.25 yr; interquartile range, 0.4-4.2 yr). Subtherapeutic concentrations were measured in 39 of 60 (65%), 43 of 48 (90%), and 35 of 49 (71%) of patients treated with amoxicillin-clavulanic acid, piperacillin-tazobactam, and meropenem, respectively. Estimates of glomerular filtration rate (eGFR; 54% increase in odds for each sd increase in value, 95% CI, 0.287-0.736; p = 0.001) and the absence of vasopressor treatment (2.8-fold greater odds, 95% CI, 1.079-7.253; p = 0.034) were independently associated with target nonattainment. We failed to identify an association between antibiotic concentrations and clinical failure. CONCLUSIONS: Subtherapeutic ß-lactam concentrations are common in critically ill children and correlate with renal function. eGFR equations may be helpful in identifying patients who may require higher dosing. Future studies should focus on the impact of subtherapeutic concentrations on clinical outcome.


Asunto(s)
Combinación Amoxicilina-Clavulanato de Potasio , beta-Lactamas , Antibacterianos/farmacocinética , Niño , Enfermedad Crítica/terapia , Humanos , Lactante , Meropenem , Combinación Piperacilina y Tazobactam , Factores de Riesgo , beta-Lactamas/farmacocinética , beta-Lactamas/uso terapéutico
7.
Pediatr Nephrol ; 35(1): 25-39, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-30374606

RESUMEN

Many critically ill patients display a supraphysiological renal function with enhanced renal perfusion and glomerular hyperfiltration. This phenomenon described as augmented renal clearance (ARC) may result in enhanced drug elimination through renal excretion mechanisms. Augmented renal clearance seems to be triggered by systemic inflammation and therapeutic interventions in intensive care. There is growing evidence that ARC is not restricted to the adult intensive care population, but is also prevalent in critically ill children. Augmented renal clearance is often overlooked due to the lack of reliable methods to assess renal function in critically ill children. Standard equations to calculate glomerular filtration rate (GFR) are developed for patients who have a steady-state creatinine production and a stable renal function. Those formulas are not reliable in critically ill patients with acutely changing GFR and tend to underestimate true GFR in patients with ARC. Tools for real-time, continuous, and non-invasive measurement of fluctuating GFR are most needed to identify changes in kidney function during critical illness and therapeutic interventions. Such devices are currently being validated and hold a strong potential to become the standard of practice. In the meantime, urinary creatinine clearance is considered the most reliable method to detect ARC in critically ill patients. Augmented renal clearance is clearly associated with subtherapeutic antimicrobial concentrations and subsequent therapeutic failure. This warrants the need for adjusted dosing regimens to optimize pharmacokinetic and pharmacodynamic target attainment. This review aims to summarize current knowledge on ARC in critically ill children, to give insight into its possible pathophysiological mechanism, to evaluate screening methods for ARC in the pediatric intensive care population, and to illustrate the effect of ARC on drug exposure, therapeutic efficacy, and clinical outcome.


Asunto(s)
Antibacterianos/farmacocinética , Cuidados Críticos/métodos , Enfermedad Crítica/terapia , Riñón/metabolismo , Eliminación Renal/fisiología , Antibacterianos/uso terapéutico , Niño , Creatinina/análisis , Creatinina/metabolismo , Tasa de Filtración Glomerular/fisiología , Humanos , Unidades de Cuidado Intensivo Pediátrico , Pruebas de Función Renal/métodos , Monitoreo Fisiológico/métodos , Resultado del Tratamiento
8.
Eur J Pediatr ; 179(5): 839-847, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-31897842

RESUMEN

Health-care professionals who prescribe medicines have the professional duty to choose medicines that are in the best interest of their individual patient, irrespective if that patient is an adult or a child. However, the availability of medicines with an appropriate label for pediatric use is lagging behind those for adults, and even available pediatric drugs are sometimes not suitable to administer to children. Consequently, health-care professionals often have no other option than to prescribe off-label medicines to children. An important reason for use of off-label medicines is to improve access to (innovative) treatments or to address medical needs and preferences of patients, especially when no other options are available. However, off-label use of medicines is in general not supported by the same level of evidence as medicines licensed for pediatric use. This may result in increased uncertainty on efficacy as well as the risk for toxicity and other side effects. In addition, liability may also be of concern, counterbalanced by professional guidelines.Conclusion: The purpose of this joint EAP/ESDPPP policy statement is to offer guidance for HCPs on when and how to prescribe off-label medicines to children and to provide recommendations for future European policy.


Asunto(s)
Uso Fuera de lo Indicado/normas , Pediatría/normas , Adolescente , Niño , Preescolar , Europa (Continente) , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Pediatría/métodos , Pautas de la Práctica en Medicina/normas , Sociedades Médicas
9.
Ther Drug Monit ; 41(1): 44-52, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30299427

RESUMEN

BACKGROUND: Amikacin is widely used to treat severe Gram-negative bacterial infections. Its peak concentration in plasma is associated with treatment efficacy. Amikacin pharmacokinetics (PK) is influenced by disease conditions, in addition to other patient characteristics. In this retrospective study, we evaluated the impact of clinical characteristics and disease condition on amikacin PK in children with burn injuries and those with cancer. METHODS: Amikacin PK data from 66 children with burn injuries and 112 children with cancer were analyzed. A population PK model was developed using the nonlinear mixed-effects modeling approach. Models were developed using NONMEM 7.3 (ICON Development Solutions, LLC, Ellicott City, MD). Data processing and visualization was performed using R packages. RESULTS: The amikacin PK data were best described by a 2-compartment model. The parameters were estimated with mean values (95% confidence intervals) as follows: central volume of distribution (V1), 5.70 L (4.64-6.76 L); central clearance, 2.12 L/h (1.79-2.46 L/h); peripheral volume of distribution (V2), 4.79 L (2.36-7.22 L); and distribution clearance (Q), 0.71 L/h (0.25-1.16 L/h). The final model identified the disease condition as a significant covariate and indicated 55% (28%-82%) higher central clearance and 17% (1%-34%) higher V1 in burn patients compared with cancer patients. Volume of distribution was significantly influenced by age and body weight. Clearance was significantly influenced by age, body weight, and creatinine clearance. Using the final PK model, we developed a workflow for selecting optimal dosing strategies for 3 representative pediatric patient profiles. CONCLUSIONS: Disease condition was significant in influencing amikacin PK in children. To reach the same target concentrations (64 mg/L peak concentration) with a daily-dose plan, burn patients need higher doses than cancer patients. Future investigations are needed to explore the impact of other diseases on amikacin disposition in children, and to prospectively validate the proposed dosing strategy.


Asunto(s)
Amicacina/farmacocinética , Antibacterianos/farmacocinética , Quemaduras/metabolismo , Neoplasias/metabolismo , Adolescente , Amicacina/uso terapéutico , Quemaduras/sangre , Niño , Preescolar , Femenino , Infecciones por Bacterias Gramnegativas/sangre , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/metabolismo , Humanos , Lactante , Masculino , Neoplasias/sangre , Estudios Retrospectivos
10.
Anal Bioanal Chem ; 411(1): 181-191, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30353218

RESUMEN

In the field of bioanalysis, dried matrix spot sampling is increasingly receiving interest, as this alternative sampling strategy offers many potential benefits over traditional sampling, including matrix volume-sparing properties. By using a microsampling strategy, e.g., volumetric absorptive microsampling (VAMS), the number of samples that can be collected from a patient can be increased, as a result of the limited sample volume that is required per sample. To date, no VAMS-based methods have been developed for the quantification of analytes in cerebrospinal fluid (CSF). The objective of this study was to develop and validate two LC-MS/MS methods for the quantification of paracetamol in dried blood and dried CSF, with both matrices sampled using VAMS. Both methods were fully validated based on internationally accepted guidelines. Paracetamol was chromatographically separated from its glucuronide and sulfate metabolites and no carry-over or unacceptable interferences were detected. The total precision (%RSD) was below 15% for all QC levels and accuracy (%bias) was below 7% (17% for the LLOQ of aqueous VAMS). The influence of the hematocrit on the recovery of blood VAMS samples appeared to be limited within the hematocrit range of 0.21 to 0.62. The blood VAMS samples were stable for 1 week if stored at 50 °C, and for at least 8 months when stored between - 80 °C and room temperature. The aqueous VAMS samples were stable for at least 9 months when stored between - 80 and 4 °C, and for 1 month when stored at room temperature. Application of the methods on external quality control material and analysis of patient samples demonstrated the validity and utility of the methods and provided a proof of concept for the analysis of CSF microsamples obtained via VAMS devices. Graphical abstract ᅟ.


Asunto(s)
Acetaminofén/sangre , Acetaminofén/líquido cefalorraquídeo , Analgésicos no Narcóticos/sangre , Analgésicos no Narcóticos/líquido cefalorraquídeo , Pruebas con Sangre Seca/instrumentación , Pruebas con Sangre Seca/métodos , Cromatografía Liquida/métodos , Pruebas con Sangre Seca/normas , Humanos , Límite de Detección , Control de Calidad , Espectrometría de Masas en Tándem/métodos
11.
Eur J Clin Pharmacol ; 75(10): 1393-1404, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31312867

RESUMEN

PURPOSE: There is a need for alternative analgosedatives such as dexmedetomidine in neonates. Given the ethical and practical difficulties, protocol design for clinical trials in neonates should be carefully considered before implementation. Our objective was to identify a protocol design suitable for subsequent evaluation of the dosing requirements for dexmedetomidine in mechanically ventilated neonates. METHODS: A published paediatric pharmacokinetic model was used to derive the dosing regimen for dexmedetomidine in a first-in-neonate study. Optimality criteria were applied to optimise the blood sampling schedule. The impact of sampling schedule optimisation on model parameter estimation was assessed by simulation and re-estimation procedures for different simulation scenarios. The optimised schedule was then implemented in a neonatal pilot study. RESULTS: Parameter estimates were more precise and similarly accurate in the optimised scenarios, as compared to empirical sampling (normalised root mean square error: 1673.1% vs. 13,229.4% and relative error: 46.4% vs. 9.1%). Most importantly, protocol deviations from the optimal design still allowed reasonable parameter estimation. Data analysis from the pilot group (n = 6) confirmed the adequacy of the optimised trial protocol. Dexmedetomidine pharmacokinetics in term neonates was scaled using allometry and maturation, but results showed a 20% higher clearance in this population compared to initial estimates obtained by extrapolation from a slightly older paediatric population. Clearance for a typical neonate, with a post-menstrual age (PMA) of 40 weeks and weight 3.4 kg, was 2.92 L/h. Extension of the study with 11 additional subjects showed a further increased clearance in pre-term subjects with lower PMA. CONCLUSIONS: The use of optimal design in conjunction with simulation scenarios improved the accuracy and precision of the estimates of the parameters of interest, taking into account protocol deviations, which are often unavoidable in this event-prone population.


Asunto(s)
Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/farmacocinética , Dexmedetomidina/administración & dosificación , Dexmedetomidina/farmacocinética , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/farmacocinética , Modelos Biológicos , Femenino , Humanos , Recién Nacido , Recien Nacido Prematuro , Masculino , Respiración Artificial
12.
Pediatr Nephrol ; 34(6): 1099-1106, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30778827

RESUMEN

BACKGROUND: Augmented renal clearance (ARC), an increase in kidney function with enhanced elimination of circulating solute, has been increasingly recognized in critically ill adults. In a pediatric intensive care setting, data are scarce. The primary objective of this study was to investigate the prevalence of ARC in critically ill children. Secondary objectives included a risk factor analysis for the development of ARC and a comparison of two methods for assessment of renal function. METHODS: In 105 critically ill children between 1 month and 15 years of age, glomerular filtration rate (GFR) was measured by means of a daily 24-h creatinine clearance (24 h ClCr) and compared to an estimated GFR using the revised Schwartz formula. Logistic regression analysis was used to identify risk factors for ARC. RESULTS: Overall, 67% of patients expressed ARC and the proportion of ARC patients decreased during consecutive days. ARC patients had a median ClCr of 142.2 ml/min/1.73m2 (IQR 47.1). Male gender and antibiotic treatment were independently associated with the occurrence of ARC. The revised Schwartz formula seems less appropriate for ARC detection. CONCLUSIONS: A large proportion of critically ill children develop ARC during their stay at the intensive care unit. Clinicians should be cautious when using Schwartz formula to detect ARC. Our findings require confirmation from large study cohorts and investigation of the relationship with clinical outcome.


Asunto(s)
Enfermedad Crítica , Tasa de Filtración Glomerular/fisiología , Riñón/fisiopatología , Adolescente , Niño , Preescolar , Creatinina/análisis , Femenino , Humanos , Lactante , Unidades de Cuidado Intensivo Pediátrico , Pruebas de Función Renal , Masculino
13.
J Antimicrob Chemother ; 72(3): 801-804, 2017 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-27999035

RESUMEN

Objectives: The objectives of this observational study were to investigate plasma protein binding and to evaluate target attainment rates of vancomycin therapy in critically ill children. Patients and methods: Paediatric ICU patients, in whom intravenous intermittent dosing (ID) or continuous dosing (CD) with vancomycin was indicated, were included. Covariates on unbound vancomycin fraction and concentration were tested using a linear mixed model analysis and attainment of currently used pharmacokinetic/pharmacodynamic (PK/PD) targets was evaluated. Clinicaltrials.gov: NCT02456974. Results: One hundred and eighty-eight plasma samples were collected from 32 patients. The unbound vancomycin fraction (median = 71.1%; IQR = 65.4%-79.7%) was highly variable within and between patients and significantly correlated with total protein and albumin concentration, which were both decreased in our population. Total trough concentration (ID) and total concentration (CD) were within the aimed target concentrations in 8% of patients. The targets of AUC/MIC ≥400 and f AUC/MIC ≥200 were achieved in 54% and 83% of patients, respectively. Unbound vancomycin concentrations were adequately predicted using the following equation: unbound vancomycin concentration (mg/L) = 5.38 + [0.71 × total vancomycin concentration (mg/L)] - [0.085 × total protein concentration (g/L)]. This final model was externally validated using 51 samples from another six patients. Conclusions: The protein binding of vancomycin in our paediatric population was lower than reported in non-critically ill adults and exhibited large variability. Higher target attainment rates were achieved when using PK/PD indices based on unbound concentrations, when compared with total concentrations. These results highlight the need for protein binding assessment in future vancomycin PK/PD research.


Asunto(s)
Antibacterianos/farmacocinética , Proteínas Sanguíneas/metabolismo , Enfermedad Crítica/terapia , Vancomicina/farmacocinética , Adolescente , Antibacterianos/sangre , Antibacterianos/uso terapéutico , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Unidades de Cuidados Intensivos , Modelos Lineales , Masculino , Pruebas de Sensibilidad Microbiana , Estudios Prospectivos , Unión Proteica , Vancomicina/sangre , Vancomicina/metabolismo , Vancomicina/uso terapéutico
14.
J Antimicrob Chemother ; 72(3): 791-800, 2017 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-27999040

RESUMEN

Objectives: The objective of this study was to characterize cefazolin serum pharmacokinetics in children before, during and after cardiopulmonary bypass (CPB), in order to derive an evidence-based dosing regimen. Patients and methods: This study included children who received cefazolin before surgical incision, before cessation of CPB and after surgery. Blood samples of total and unbound cefazolin concentrations were collected before, during and after CPB. The cefazolin concentration-time profiles were analysed using population pharmacokinetic modelling and predictors for interindividual variability in pharmacokinetic parameters were investigated. Subsequently, optimized dosing regimens were developed using stochastic simulations. Clinicaltrials.gov: NCT02749981. Results: A total of 494 total and unbound cefazolin concentrations obtained from 56 children (aged 6 days to 15 years) were included. A two-compartment model with first-order elimination plus an additional compartment for the effect of CPB best described the data. Clearance (1.56 L/h), central volume (1.93 L) and peripheral volume (2.39 L) were allometrically scaled by body weight. The estimated glomerular filtration rate (eGFR) was identified as a covariate on clearance and the serum albumin concentration was associated with maximum protein binding capacity. Our simulations showed that an additional bolus dose at the start of CPB improves the PTA in typical patients from 59% to >94%. Prolonged surgery and preserved renal function (i.e. drop in eGFR <25%) had a negative impact on PTA. Conclusions: We propose an optimized dosing regimen for cefazolin during cardiac surgery in paediatric patients to avoid treatment failure due to inadequate antibiotic prophylaxis.


Asunto(s)
Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Profilaxis Antibiótica , Puente Cardiopulmonar , Cefazolina/administración & dosificación , Cefazolina/farmacocinética , Adolescente , Antibacterianos/sangre , Cefazolina/sangre , Niño , Preescolar , Simulación por Computador , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Población , Estudios Prospectivos
15.
J Antimicrob Chemother ; 72(7): 2002-2011, 2017 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-28387840

RESUMEN

Objectives: To characterize the population pharmacokinetics of piperacillin and tazobactam in critically ill infants and children, in order to develop an evidence-based dosing regimen. Patients and methods: This pharmacokinetic study enrolled patients admitted to the paediatric ICU for whom intravenous piperacillin/tazobactam (8:1 ratio) was indicated (75 mg/kg every 6 h based on piperacillin). Piperacillin/tazobactam concentrations were measured by an LC-MS/MS method. Pharmacokinetic data were analysed using non-linear mixed effects modelling. Results: Piperacillin and tazobactam blood samples were collected from 47 patients (median age 2.83 years; range 2 months to 15 years). Piperacillin and tazobactam disposition was best described by a two-compartment model that included allometric scaling and a maturation function to account for the effect of growth and age. Mean clearance estimates for piperacillin and tazobactam were 4.00 and 3.01 L/h for a child of 14 kg. Monte Carlo simulations showed that an intermittent infusion of 75 mg/kg (based on piperacillin) every 4 h over 2 h, 100 mg/kg every 4 h given over 1 h or a loading dose of 75 mg/kg followed by a continuous infusion of 300 mg/kg/24 h were the minimal requirements to achieve the therapeutic targets for piperacillin (60% f T >MIC >16 mg/L). Conclusions: Standard intermittent dosing regimens do not ensure optimal piperacillin/tazobactam exposure in critically ill patients, thereby risking treatment failure. The use of a loading dose followed by a continuous infusion is recommended for treatment of severe infections in children >2 months of age.


Asunto(s)
Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Infecciones Bacterianas/tratamiento farmacológico , Enfermedad Crítica , Ácido Penicilánico/análogos & derivados , Adolescente , Antibacterianos/sangre , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Lactante , Infusiones Intravenosas , Masculino , Pruebas de Sensibilidad Microbiana , Método de Montecarlo , Ácido Penicilánico/administración & dosificación , Ácido Penicilánico/sangre , Ácido Penicilánico/farmacocinética , Piperacilina/administración & dosificación , Piperacilina/sangre , Piperacilina/farmacocinética , Combinación Piperacilina y Tazobactam , Estudios Prospectivos , Tazobactam
18.
Antimicrob Agents Chemother ; 59(11): 7027-35, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26349821

RESUMEN

There is little data available to guide amoxicillin-clavulanic acid dosing in critically ill children. The primary objective of this study was to investigate the pharmacokinetics of both compounds in this pediatric subpopulation. Patients admitted to the pediatric intensive care unit (ICU) in whom intravenous amoxicillin-clavulanic acid was indicated (25 to 35 mg/kg of body weight every 6 h) were enrolled. Population pharmacokinetic analysis was conducted, and the clinical outcome was documented. A total of 325 and 151 blood samples were collected from 50 patients (median age, 2.58 years; age range, 1 month to 15 years) treated with amoxicillin and clavulanic acid, respectively. A three-compartment model for amoxicillin and a two-compartment model for clavulanic acid best described the data, in which allometric weight scaling and maturation functions were added a priori to scale for size and age. In addition, plasma cystatin C and concomitant treatment with vasopressors were identified to have a significant influence on amoxicillin clearance. The typical population values of clearance for amoxicillin and clavulanic acid were 17.97 liters/h/70 kg and 12.20 liters/h/70 kg, respectively. In 32% of the treated patients, amoxicillin-clavulanic acid therapy was stopped prematurely due to clinical failure, and the patient was switched to broader-spectrum antibiotic treatment. Monte Carlo simulations demonstrated that four-hourly dosing of 25 mg/kg was required to achieve the therapeutic target for both amoxicillin and clavulanic acid. For patients with augmented renal function, a 1-h infusion was preferable to bolus dosing. Current published dosing regimens result in subtherapeutic concentrations in the early period of sepsis due to augmented renal clearance, which risks clinical failure in critically ill children, and therefore need to be updated. (This study has been registered at Clinicaltrials.gov as an observational study [NCT02456974].).


Asunto(s)
Combinación Amoxicilina-Clavulanato de Potasio/administración & dosificación , Combinación Amoxicilina-Clavulanato de Potasio/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Adolescente , Combinación Amoxicilina-Clavulanato de Potasio/uso terapéutico , Antibacterianos/uso terapéutico , Niño , Preescolar , Enfermedad Crítica , Femenino , Humanos , Lactante , Masculino , Método de Montecarlo , Estudios Prospectivos , Sepsis/prevención & control
19.
Sci Rep ; 14(1): 1657, 2024 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-38238516

RESUMEN

Prospective audit with feedback during infectious diseases ward rounds (IDWR) is a common antimicrobial stewardship (AMS) practice on the Paediatric Intensive Care Unit (PICU). These interdisciplinary meetings rely on the quality of handover, with high risk of omission of information. We developed an electronic platform integrating infection-related patient data (COSARAPed). In the mixed PICU of a Belgian tertiary hospital we conducted an observational prospective cohort study comparing patient handovers during IDWRs using the COSARAPed-platform to those with access only to conventional resources. The quality of handover was investigated directly by assessment if the narrative was in accordance with Situation-Background-Assessment-Recommendation principles and if adequate demonstration of diagnostic information occurred, and also indirectly by registration if this was only achieved after intervention by the non-presenting AMS team members. We also recorded all AMS-recommendations. During a 6-month study period, 24 IDWRs and 82 patient presentations were assessed. We could only find a statistically significant advantage in favor of COSARAPed by indirect evaluation. We registered 92 AMS-recommendations, mainly resulting in reduced antibiotic pressure. We concluded that the IDWR is an appropriate platform for AMS on the PICU and that the utilisation of COSARAPed may enhance the quality of patient handover.


Asunto(s)
Enfermedades Transmisibles , Tecnología de la Información , Niño , Humanos , Comunicación Interdisciplinaria , Estudios Prospectivos , Unidades de Cuidado Intensivo Pediátrico , Comunicación
20.
Clin Pharmacokinet ; 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38955946

RESUMEN

BACKGROUND AND OBJECTIVE: The interstitial fluid of tissues is the effect site for antibiotics targeting extracellular pathogens. Microdialysis studies investigating these concentrations in muscle and subcutaneous tissue have reported notable variability in tissue penetration. This study aimed to comprehensively summarise the existing data on interstitial fluid penetration in these tissues and to identify potential factors influencing antibiotic distribution. METHODS: A literature review was conducted, focusing on subcutaneous and intramuscular microdialysis studies of antibiotics in both adult healthy volunteers and patients. Random-effect meta-analyses were used to aggregate effect size estimates of tissue penetration. The primary parameter of interest was the unbound penetration ratio, which represents the ratio of the area under the concentration-time curve in interstitial fluid relative to the area under the concentration-time curve in plasma, using unbound concentrations. RESULTS: In total, 52 reports were incorporated into this analysis. The unbound antibiotic exposure in the interstitial fluid of healthy volunteers was, on average, 22% lower than in plasma. The unbound penetration ratio values were higher after multiple dosing but did not significantly differ between muscle and subcutaneous tissue. Unbound penetration ratio values were lower for acids and bases compared with neutral antibiotics. Neither the molecular weight nor the logP of the antibiotics accounted for the variations in the unbound penetration ratio. Obesity was associated with lower interstitial fluid penetration. Conditions such as sepsis, tissue inflammation and tissue ischaemia were not significantly associated with altered interstitial fluid penetration. CONCLUSIONS: This study highlights the variability and generally lower exposure of unbound antibiotics in the subcutaneous and intramuscular interstitial fluid compared with exposure in plasma. Future research should focus on understanding the therapeutic relevance of these differences and identify key covariates that may influence them.

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