First name
Nicole
Middle name
R
Last name
Zane

Title

Effect of Cystatin C on Vancomycin Clearance Estimation in Critically Ill Children Using a Population Pharmacokinetic Modeling Approach.

Year of Publication

2020

Date Published

2020 Sep 15

ISSN Number

1536-3694

Abstract

<p><strong>BACKGROUND: </strong>Vancomycin is eliminated via glomerular filtration, but current approaches to estimate kidney function in children are unreliable. The authors sought to compare the suitability of cystatin C (CysC)-based glomerular filtration rate equations with the most commonly used creatinine-based equation, bedside Schwartz, to estimate vancomycin clearance (CL).</p>

<p><strong>METHODS: </strong>This prospective observational study enrolled critically ill patients (2-18 years) receiving intravenous (IV) vancomycin at the Children's Hospital of Philadelphia during December 2015-November 2017. Vancomycin levels were collected during clinical care and at 3 times during a single dosing interval. Plasma CysC was measured within 24 hours prior to IV vancomycin (baseline) initiation or immediately following enrollment, as well as along with the third pharmacokinetic (PK) sample. Nonlinear mixed effects modeling was performed using NONMEM software. Covariate selection was used to test model fit with inclusion of estimated glomerular filtration rate (eGFR) on CL using bedside Schwartz versus various published CysC-based equations.</p>

<p><strong>RESULTS: </strong>In total, 83 vancomycin levels were obtained from 20 children. Median age was 12.7 years; 6 patients were female. A one-compartment model best described the data; CL was allometrically scaled to 0.75. During covariate selection, inclusion of eGFR calculated using a CysC-based equation significantly improved model fit (reduction in objective function value [OFV] range: -17.191 to -18.704) than bedside Schwartz ([INCREMENT]OFV -12.820). Including the full age spectrum equation, an eGFR equation based on both creatinine and CysC, led to the largest OFV reduction (-22.913); female sex was also a significant covariate of CL in the model. Final model pharmacokinetic indices were CL = 0.29 L/hr/kg and volume of distribution = 0.48 L/kg.</p>

<p><strong>CONCLUSIONS: </strong>CysC-based equations help better estimate vancomycin CL than bedside Schwartz in critically ill children.</p>

DOI

10.1097/FTD.0000000000000796

Alternate Title

Ther Drug Monit

PMID

32947559

Title

Administration and Dosing of Systemic Antifungal Agents in Pediatric Patients.

Year of Publication

2020

Date Published

2020 Jan 23

ISSN Number

1179-2019

Abstract

<p>Neonates and immunosuppressed/immunocompromised pediatric patients are at high risk of invasive fungal diseases. Appropriate antifungal selection and optimized dosing are imperative to the successful prevention and treatment of these life-threatening infections. Conventional amphotericin B was the mainstay of antifungal therapy for many decades, but dose-limiting nephrotoxicity and infusion-related adverse events impeded its use. Despite the development of several new antifungal classes and agents in the past 20&nbsp;years, and their now routine use in at-risk pediatric populations, data to guide the optimal dosing of antifungals in children are limited. This paper reviews the spectra of activity for approved antifungal agents and summarizes the current literature specific to pediatric patients regarding pharmacokinetic/pharmacodynamic data, dosing, and therapeutic drug monitoring.</p>

DOI

10.1007/s40272-020-00379-2

Alternate Title

Paediatr Drugs

PMID

31974859

Title

Development and validation of a volumetric absorptive microsampling- liquid chromatography mass spectrometry method for the analysis of cefepime in human whole blood: Application to pediatric pharmacokinetic study.

Year of Publication

2020

Number of Pages

113002

Date Published

2020 Feb 05

ISSN Number

1873-264X

Abstract

<p>Cefepime is a fourth-generation cephalosporin antibiotic with an extended spectrum of activity against many Gram-positive and Gram-negative bacteria. There is a growing need to develop sensitive, small volume assays, along with less invasive sample collection to facilitate pediatric pharmacokinetic clinical trials and therapeutic drug monitoring. The volumetric absorptive microsampling (VAMS™) approach provides an accurate and precise collection of a fixed volume of blood (10 μL), reducing or eliminating the volumetric blood hematocrit assay-bias associated with the dried blood spotting technique. We developed a high-performance liquid chromatographic method with tandem mass spectrometry detection for quantification of cefepime. Sample extraction from VAMS™ devices, followed by reversed-phase chromatographic separation and selective detection using tandem mass spectrometry with a 4 min runtime per sample was employed. Standard curves were linear between 0.1-100 μg/mL for cefepime. Intra- and inter-day accuracies were within 95.4-113% and precision (CV) was &lt; 15 % based on a 3-day validation study. Recoveries ranged from 40.8 to 62.1% and the matrix effect was within 89.5-96.7% for cefepime. Cefepime was stable in human whole blood under assay conditions (3 h at room temperature, 24 h in autosampler post-extraction). Cefepime was also stable for at least 1 week (7 days) at 4 °C, 1 month (39 days) at -20 °C and 3 months (91 days) at -78 °C as dried microsamples. This assay provides an efficient quantitation of cefepime and was successfully implemented for the analysis of whole blood microsamples in a pediatric clinical trial.</p>

DOI

10.1016/j.jpba.2019.113002

Alternate Title

J Pharm Biomed Anal

PMID

31785929

Title

Mechanisms of antimicrobial-induced nephrotoxicity in children.

Year of Publication

2019

Date Published

2019 Aug 01

ISSN Number

1460-2091

Abstract

<p>Drug-induced nephrotoxicity is responsible for 20% to 60% of cases of acute kidney injury in hospitalized patients and is associated with increased morbidity and mortality in both children and adults. Antimicrobials are one of the most common classes of medications prescribed globally and also among the most common causes of nephrotoxicity. A broad range of antimicrobial agents have been associated with nephrotoxicity, but the features of kidney injury vary based on the agent, its mechanism of injury and the site of toxicity within the kidney. Distinguishing nephrotoxicity caused by an antimicrobial agent from other potential inciting factors is important to facilitate both early recognition of drug toxicity and prompt cessation of an offending drug, as well as to avoid unnecessary discontinuation of an innocuous therapy. This review will detail the different types of antimicrobial-induced nephrotoxicity: acute tubular necrosis, acute interstitial nephritis and obstructive nephropathy. It will also describe the mechanism of injury caused by specific antimicrobial agents and classes (vancomycin, aminoglycosides, polymyxins, antivirals, amphotericin B), highlight the toxicodynamics of these drugs and provide guidance on administration or monitoring practices that can mitigate toxicity, when known. Particular attention will be paid to paediatric patients, when applicable, in whom nephrotoxin exposure is an often-underappreciated cause of kidney injury.</p>

DOI

10.1093/jac/dkz325

Alternate Title

J. Antimicrob. Chemother.

PMID

31369087

Title

Vancomycin Prescribing and Therapeutic Drug Monitoring in Children With and Without Acute Kidney Injury After Cardiac Arrest.

Year of Publication

2019

Date Published

2019 Mar 12

ISSN Number

1179-2019

Abstract

<p><strong>BACKGROUND: </strong>Acute kidney injury (AKI) commonly occurs after cardiac arrest. Those subsequently treated with vancomycin are at additional risk for drug-induced kidney injury.</p>

<p><strong>OBJECTIVE: </strong>We aimed to determine whether opportunities exist for improved drug monitoring after cardiac arrest.</p>

<p><strong>METHODS: </strong>This was a retrospective cohort study of children aged 30&nbsp;days-17&nbsp;years treated after cardiac arrest in an intensive care unit from January 2010 to September 2014 who received vancomycin within 24&nbsp;h of arrest. Vancomycin dosing and monitoring were compared between those with and without AKI, with AKI defined as pRIFLE (pediatric risk, injury, failure, loss, end-stage renal disease) stage 2-3 AKI at day 5 using Schwartz formula-calculated estimated glomerular filtration rate (eGFR).</p>

<p><strong>RESULTS: </strong>Of 43 children, 16 (37%) had AKI at day 5. Age, arrest duration, median time to first vancomycin dose, and the number of doses before and time to first vancomycin concentration measurement were similar between groups. Children with AKI had higher initial vancomycin concentrations than those without AKI (median 16 vs. 7&nbsp;mg/L; p = 0.003). A concentration was not measured before the second dose in 44% of children with AKI. Initial eGFR predicted day 5 AKI. In children with AKI, the initial eGFR was lower in those with than those without a concentration measurement before the second dose (29&nbsp;mL/min/1.73&nbsp;m [interquartile range (IQR) 23-47] vs. 52 [IQR 50-57]; p = 0.03) but well below normal in both.</p>

<p><strong>CONCLUSIONS: </strong>In children with AKI after cardiac arrest, decreased vancomycin clearance was evident early, and early monitoring was not performed universally in those with low initial eGFR. Earlier vancomycin therapeutic drug monitoring is indicated in this high-risk population.</p>

DOI

10.1007/s40272-019-00328-8

Alternate Title

Paediatr Drugs

PMID

30864056

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