scholarly journals Model-Informed Precision Dosing of Antibiotics in Pediatric Patients: A Narrative Review

2021 ◽  
Vol 9 ◽  
Author(s):  
Alan Abdulla ◽  
Angela E. Edwina ◽  
Robert B. Flint ◽  
Karel Allegaert ◽  
Enno D. Wildschut ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Pediatric Patients ◽  
Significant Proportion ◽  
Patient Characteristics ◽  
Narrative Review ◽  
Therapeutic Drug ◽  
Analysis Model ◽  
Age Related ◽  
Co Morbidity ◽  
Optimal Drug

Optimal pharmacotherapy in pediatric patients with suspected infections requires understanding and integration of relevant data on the antibiotic, bacterial pathogen, and patient characteristics. Because of age-related physiological maturation and non-maturational covariates (e.g., disease state, inflammation, organ failure, co-morbidity, co-medication and extracorporeal systems), antibiotic pharmacokinetics is highly variable in pediatric patients and difficult to predict without using population pharmacokinetics models. The intra- and inter-individual variability can result in under- or overexposure in a significant proportion of patients. Therapeutic drug monitoring typically covers assessment of pharmacokinetics and pharmacodynamics, and concurrent dose adaptation after initial standard dosing and drug concentration analysis. Model-informed precision dosing (MIPD) captures drug, disease, and patient characteristics in modeling approaches and can be used to perform Bayesian forecasting and dose optimization. Incorporating MIPD in the electronic patient record system brings pharmacometrics to the bedside of the patient, with the aim of a consisted and optimal drug exposure. In this narrative review, we evaluated studies assessing optimization of antibiotic pharmacotherapy using MIPD in pediatric populations. Four eligible studies involving amikacin and vancomycin were identified from 418 records. Key articles, independent of year of publication, were also selected to highlight important attributes of MIPD. Although very little research has been conducted until this moment, the available data on vancomycin indicate that MIPD is superior compared to conventional dosing strategies with respect to target attainment. The utility of MIPD in pediatrics needs to be further confirmed in frequently used antibiotic classes, particularly aminoglycosides and beta-lactams.

scholarly journals Pharmacokinetics of Daptomycin in Critically Ill Pediatric Patients

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Charalampos Antachopoulos ◽  
Stavroula Ilia ◽  
Paschalis Kadiltzoglou ◽  
Eirini Baira ◽  
Aristides Dokoumetzidis ◽  
...  
Keyword(s):  
Critically Ill ◽  
Drug Exposure ◽  
Pediatric Patients ◽  
Plasma Concentrations ◽  
Therapeutic Drug ◽  
Burn Patients ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time ◽  
Optimal Drug

ABSTRACT The pharmacokinetics of daptomycin (10 mg/kg once daily) was studied in 4 critically ill pediatric patients aged 8 to 14 yrs. The area under the concentration-time curve from time zero to infinity (AUC 0–∞ ) of plasma concentrations on day 1 ranged between 123.8 to 663.9 μg · h/ml, with lower values observed in septic and burn patients; clearance ranged from 15.1 to 80.7 ml/h/kg. Higher-than-recommended doses of daptomycin may be needed in septic children to ensure optimal drug exposure. Interpatient variability may suggest a role for therapeutic drug monitoring.

scholarly journals Clinical Validation of the Analysis of Fluconazole in Oral Fluid in Hospitalized Children

2014 ◽  
Vol 58 (11) ◽  
pp. 6742-6746 ◽  
Author(s):  
Kim C. M. van der Elst ◽  
Manouche van Alst ◽  
Marjolijn N. Lub-de Hooge ◽  
Kai van Hateren ◽  
Jos G. W. Kosterink ◽  
...  
Keyword(s):  
Oral Fluid ◽  
Drug Exposure ◽  
Pediatric Patients ◽  
Pearson Correlation ◽  
Volume Of Distribution ◽  
Therapeutic Drug ◽  
Pearson Correlation Test ◽  
Liquid Chromatography Tandem Mass ◽  
Paired Serum ◽  
At Home

ABSTRACTFluconazole is a first-line antifungal agent for the treatment and prophylaxis of invasive candidiasis in pediatric patients. Pediatric patients are at risk of suboptimal drug exposure, due to developmental changes in gastrointestinal and renal function, metabolic capacity, and volume of distribution. Therapeutic drug monitoring (TDM) can therefore be useful to prevent underexposure of fluconazole in children and infants. Children, however, often fear needles and can have difficult vascular access. The purpose of this study was to develop and clinically validate a method of analysis to determine fluconazole in oral fluid in pediatric patients. Twenty-one paired serum and oral fluid samples were obtained from 19 patients and were analyzed using a validated liquid chromatography-tandem mass spectrometry (LC–MS-MS) method after cross-validation between serum and oral fluid. The results were within accepted ranges for accuracy and precision, and samples were stable at room temperature for at least 17 days. A Pearson correlation test for the fluconazole concentrations in serum and oral fluid showed a correlation coefficient of 0.960 (P< 0.01). The mean oral fluid-to-serum concentration ratio was 0.99 (95% confidence interval [CI], 0.88 to 1.10) with Bland-Altman analysis. In conclusion, an oral fluid method of analysis was successfully developed and clinically validated for fluconazole in pediatric patients and can be a noninvasive, painless alternative to perform TDM of fluconazole when blood sampling is not possible or desirable. When patients receive prolonged courses of antifungal treatment and use fluconazole at home, this method of analysis can extend the possibilities of TDM for patients at home.

Axitinib for first-line metastatic renal cell carcinoma (mRCC): Overall efficacy and pharmacokinetic (PK) analyses from a randomized phase II study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4503-4503 ◽  
Author(s):  
Brian I. Rini ◽  
Viktor Grünwald ◽  
Mayer N. Fishman ◽  
Bohuslav Melichar ◽  
Takeshi Ueda ◽  
...  
Keyword(s):  
Phase Ii ◽  
Drug Exposure ◽  
Objective Response ◽  
Dose Titration ◽  
Therapeutic Drug ◽  
First Line ◽  
Antihypertensive Medications ◽  
Double Blind ◽  
Randomized Phase Ii ◽  
Optimal Drug

4503 Background: Axitinib is a potent, selective, second-generation inhibitor of vascular endothelial growth factor receptors with efficacy in mRCC. Due to PK and pharmacodynamic variability, some patients have sub-optimal drug exposures at the standard 5-mg twice daily (BID) dose. Prior analyses indicated higher drug exposure enhanced efficacy; thus, dose titration based on individual tolerability may optimize exposure and improve outcomes. A randomized phase II trial evaluated the efficacy and safety of axitinib dose titration from 5 mg BID to a maximum of 10 mg BID in first-line mRCC. Methods: Patients with treatment-naïve mRCC received axitinib 5 mg BID for a 4-week lead-in period (cycle 1). Then, patients with 2 consecutive weeks of blood pressure (BP) ≤150/90 mmHg, no axitinib-related toxicities >grade 2, no dose reductions, and ≤2 antihypertensive medications were randomized in a double-blind fashion to axitinib 5 mg BID + dose titration with either axitinib (arm A) or placebo (arm B); those ineligible for randomization continued with same dose (arm C). Primary endpoint is objective response rate (ORR). Serial 6-hr PK sampling and 24-hr ambulatory BP monitoring (ABPM) were performed on cycle 1 day 15 in a subset of patients. Results: In all, 203 patients were accrued; 112 randomized to arms A or B, and 91 in arm C. As of July 1, 2011, ORR (95% confidence interval [CI]) was 40.2% (31.0, 49.9) in A+B (blinded pooled analysis) and 56.0% (45.2, 66.4) in C. Median progression-free survival (mPFS) (95% CI) was 13.7 mo (9.2, not estimable [NE]) in A+B and 12.2 mo (8.6, 16.7) in C. Patients with drug exposure above therapeutic threshold (AUC24 ≥300 ng·h/mL; n=27) on cycle 1 day 15 had longer mPFS and higher ORR than those with sub-therapeutic exposure (n=25) (mPFS [95% CI]: 13.9 mo [12.2, NE] vs 8.3 mo [5.5, NE]; ORR: 59% vs 48%). Patients with mean increases of diastolic BP (ΔdBP) ≥15 mmHg (n=18) per ABPM had higher ORR than those with ΔdBP <15 mmHg (n=36) (61% vs 53%). Conclusions: Axitinib is effective in first-line treatment of mRCC, with high ORR and mPFS >1 yr. Preliminary results suggest therapeutic drug exposure and ΔdBP ≥15 mmHg on cycle 1 day 15 may be associated with better outcomes.

scholarly journals Association between voriconazole exposure and Sequential Organ Failure Assessment (SOFA) score in critically ill patients

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0260656
Author(s):  
Anne-Lise Bienvenu ◽  
Pierre Pradat ◽  
Alexandra Plesa ◽  
Vincent Leclerc ◽  
Vincent Piriou ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Critically Ill ◽  
Sofa Score ◽  
Critically Ill Patients ◽  
Drug Exposure ◽  
Therapeutic Drug ◽  
Multicenter Cohort Study ◽  
Large Variability ◽  
Optimal Drug ◽  
The Impact

Therapeutic drug monitoring (TDM) is essential for voriconazole to ensure optimal drug exposure, mainly in critically ill patients for whom voriconazole demonstrated a large variability. The study aimed at describing factors associated with trough voriconazole concentrations in critically ill patients and evaluating the impact of voriconazole concentrations on adverse effects. A 2-year retrospective multicenter cohort study (NCT04502771) was conducted in six intensive care units. Adult patients who had at least one voriconazole TDM were included. Univariable and multivariable linear regression analyses were performed to identify predictors of voriconazole concentrations, and univariable logistic regression analysis, to study the relationship between voriconazole concentrations and adverse effects. During the 2-year study period, 70 patients were included. Optimal trough voriconazole concentrations were reported in 37 patients (52.8%), subtherapeutic in 20 (28.6%), and supratherapeutic in 13 (18.6%). Adverse effects were reported in six (8.6%) patients. SOFA score was identified as a factor associated with an increase in voriconazole concentration (p = 0.025), mainly in the group of patients who had SOFA score ≥ 10. Moreover, an increase in voriconazole concentration was shown to be a risk factor for occurrence of adverse effects (p = 0.011). In that respect, critically ill patients who received voriconazole treatment must benefit from a TDM, particularly if they have a SOFA score ≥ 10. Indeed, identifying patients who are overdosed will help to prevent voriconazole related adverse effects. This result is of utmost importance given the recognized COVID-19-associated pulmonary aspergillosis in ICU patients for whom voriconazole is among the recommended first-line treatment.

scholarly journals A Narrative Review on Sarcopenia in Type 2 Diabetes Mellitus: Prevalence and Associated Factors

Nutrients ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 183
Author(s):  
Anna Izzo ◽  
Elena Massimino ◽  
Gabriele Riccardi ◽  
Giuseppe Della Pepa
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Elderly Population ◽  
The Elderly ◽  
Narrative Review ◽  
Macrovascular Complications ◽  
Diabetic Patients ◽  
Age Related

Type 2 diabetes mellitus (T2DM) represents a major health burden for the elderly population, affecting approximately 25% of people over the age of 65 years. This percentage is expected to increase dramatically in the next decades in relation to the increased longevity of the population observed in recent years. Beyond microvascular and macrovascular complications, sarcopenia has been described as a new diabetes complication in the elderly population. Increasing attention has been paid by researchers and clinicians to this age-related condition—characterized by loss of skeletal muscle mass together with the loss of muscle power and function—in individuals with T2DM; this is due to the heavy impact that sarcopenia may have on physical and psychosocial health of diabetic patients, thus affecting their quality of life. The aim of this narrative review is to provide an update on: (1) the risk of sarcopenia in individuals with T2DM, and (2) its association with relevant features of patients with T2DM such as age, gender, body mass index, disease duration, glycemic control, presence of microvascular or macrovascular complications, nutritional status, and glucose-lowering drugs. From a clinical point of view, it is necessary to improve the ability of physicians and dietitians to recognize early sarcopenia and its risk factors in patients with T2DM in order to make appropriate therapeutic approaches able to prevent and treat this condition.

scholarly journals Survivors of Hell: Resilience Amongst Unaccompanied Minor Refugees and Implications for Treatment- a Narrative Review

2021 ◽  
Author(s):  
Irene Mateos Rodriguez ◽  
Veronika Dobler
Keyword(s):  
Mental Health ◽  
Living Arrangements ◽  
Mental Health Problems ◽  
Significant Proportion ◽  
Narrative Review ◽  
Behaviour Problem ◽  
Positive Relationships ◽  
Theoretical Understanding ◽  
Problem Solving Skills ◽  
User Perspectives

AbstractApproximately half of the world’s displaced population are children and a significant proportion of these are unaccompanied asylum-seeking children (UASC). UASC are the most vulnerable of all refugee populations. Up to 90% of UASC have been subjected to exploitation, including trafficking or being drafted into military groups. Having survived the perils of flight, UASC are confronted with continued challenges, including the uncertainties regarding their residential rights in host counties. Unsurprisingly, the prevalence of mental health problems is higher amongst UASC than in any other refugee group. Yet, Mental Health and Psychosocial Support (MHPSS) appears to neither reach nor engage UASC. This begs for re-examination of what and how MHPSS is offered. Despite high levels of adversity, UASC often have considerable resilience, and make remarkable recoveries. However, literature exploring their resources or their own views of what helps or hinders recovery is scarce. In this narrative review, we explore individual and systemic factors promoting recovery in UASC. We consider theoretical understanding of resilience, emerging data and user perspectives. From these we deduct four areas of resilience in UASC: Individual factors – prosocial behaviour, problem-solving skills; Lifetime relationships – positive early family relationships, connection with family and country of origin, positive peer and adult relationships in host country; Acculturation – integration of own and new culture, positive relationships with prosocial institutions; Care arrangements – supported but less restrictive living arrangements. We suggest, MHPSS may need to focus on enhancing social networks, including connectedness with positive relationships in the home-country, life-history work with a focus on resource-building experiences in addition to trauma, and promoting integration of old and new cultural values. We also conclude that despite growing data, there is a gap in both eliciting user perspectives and understanding adaptive resources, especially those emerging during early development and within their cultural setting.

scholarly journals Vascular and haemodynamic issues of brain ageing

2021 ◽  
Author(s):  
Lucy Beishon ◽  
Rebecca H. Clough ◽  
Meeriam Kadicheeni ◽  
Tamara Chithiramohan ◽  
Ronney B. Panerai ◽  
...  
Keyword(s):  
Significant Proportion ◽  
Cerebrovascular Diseases ◽  
Healthy Ageing ◽  
Cognitive Stimulation ◽  
High Morbidity ◽  
Age Related ◽  
Brain Ageing ◽  
Haemodynamic Changes ◽  
Normal Ageing ◽  
The Individual

AbstractThe population is ageing worldwide, thus increasing the burden of common age-related disorders to the individual, society and economy. Cerebrovascular diseases (stroke, dementia) contribute a significant proportion of this burden and are associated with high morbidity and mortality. Thus, understanding and promoting healthy vascular brain ageing are becoming an increasing priority for healthcare systems. In this review, we consider the effects of normal ageing on two major physiological processes responsible for vascular brain function: Cerebral autoregulation (CA) and neurovascular coupling (NVC). CA is the process by which the brain regulates cerebral blood flow (CBF) and protects against falls and surges in cerebral perfusion pressure, which risk hypoxic brain injury and pressure damage, respectively. In contrast, NVC is the process by which CBF is matched to cerebral metabolic activity, ensuring adequate local oxygenation and nutrient delivery for increased neuronal activity. Healthy ageing is associated with a number of key physiological adaptations in these processes to mitigate age-related functional and structural declines. Through multiple different paradigms assessing CA in healthy younger and older humans, generating conflicting findings, carbon dioxide studies in CA have provided the greatest understanding of intrinsic vascular anatomical factors that may mediate healthy ageing responses. In NVC, studies have found mixed results, with reduced, equivalent and increased activation of vascular responses to cognitive stimulation. In summary, vascular and haemodynamic changes occur in response to ageing and are important in distinguishing “normal” ageing from disease states and may help to develop effective therapeutic strategies to promote healthy brain ageing.

Multi-Disciplinary Skull Base Conference and its Effects on Patient Management

2021 ◽  
pp. 000348942110212
Author(s):  
Nathan Kemper ◽  
Scott B. Shapiro ◽  
Allie Mains ◽  
Noga Lipschitz ◽  
Joseph Breen ◽  
...  
Keyword(s):  
Skull Base ◽  
Medical Center ◽  
Academic Medical Center ◽  
Significant Proportion ◽  
Internal Auditory Canal ◽  
Patient Characteristics ◽  
Management Plan ◽  
Case Review ◽  
Retrospective Case ◽  
Lateral Skull Base

Objective: Examine the effects of a multi-disciplinary skull base conference (MDSBC) on the management of patients seen for skull base pathology in a neurotology clinic. Methods: Retrospective case review of patients who were seen in a neurotology clinic at a tertiary academic medical center for pathology of the lateral skull base and were discussed at an MDSBC between July 2019 and February 2020. Patient characteristics, nature of the skull base pathology, and pre- and post-MDSBC plan of care was categorized. Results: A total of 82 patients with pathology of the lateral skull base were discussed at a MDSBC during an 8-month study period. About 54 (65.9%) had a mass in the internal auditory canal and/or cerebellopontine angle while 28 (34.1%) had other pathology of the lateral skull base. Forty-nine (59.8%) were new patients and 33 (40.2%) were established. The management plan changed in 11 (13.4%, 7.4-22.6 95% CI) patients as a result of the skull base conference discussion. The planned management changed from some form of treatment to observation in 4 patients, and changed from observation to some form of treatment in 4 patients. For 3 patients who underwent surgery, the planned approach was altered. Conclusions: For a significant proportion of patients with pathology of the lateral skull base, the management plan changed as a result of discussion at an MDSBC. Although participants of a MDSBC would agree of its importance, it is unclear how an MDSBC affects patient outcomes.

Heritability of Longitudinal Measures of Body Mass Index and Lipid and Lipoprotein Levels in Aging Twins

2007 ◽  
Vol 10 (5) ◽  
pp. 703-711 ◽  
Author(s):  
Ellen L. Goode ◽  
Stacey S. Cherny ◽  
Joe C. Christian ◽  
Gail P. Jarvik ◽  
Mariza de Andrade
Keyword(s):  
Body Mass Index ◽  
Body Mass ◽  
Genetic Factors ◽  
Significant Proportion ◽  
Lipoprotein Cholesterol ◽  
Equation Modeling ◽  
Shared Environment ◽  
Significant Contributor ◽  
Age Related ◽  
Over Time

AbstractBody-mass index (BMI), total cholesterol (TC), lowdensity lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels are known to be highly heritable. We evaluated the genetic and environmental relationships of these measures over time in an analysis of twin pairs. Monozygotic (235 pairs) and dizygotic (260 pairs) male twins were participants in the National Heart Lung and Blood Institute Veteran Twin Study, and were followed with three clinical exams from mean age 48 years to mean age 63 years. Structural equation modeling (SEM) with adjustment forAPOEgenotype (a significant contributor to TC and LDL-C) was used to assess longitudinal patterns of heritability. Results indicated a contribution of genetic factors to BMI, TC, LDL-C, HLD-C, and TG. Modest increases over time were observed in the heritability of BMI (from 0.48 to 0.61), TC (from 0.46 to 0.57), LDL-C (from 0.49 to 0.64), and HDL-C (from 0.50 to 0.62), but this trend was not present for TG. There was a corresponding decrease in shared environmental influences over time for these traits, although shared environment was a significant contributor only for HDL-C. Moreover, we observed that genetic influences for all measures were significantly correlated over time, and we found no evidence of age-specific genetic effects. In summary, longitudinal analyses of twin data indicate that genetic factors do not account for a significant proportion of the variation in age-related changes of BMI or lipid and lipoprotein levels.

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