A Pharmacokinetic Analysis of Tobramycin in Patients Less than Five Years of Age with Cystic Fibrosis: Assessment of Target Attainment with Extended-Interval Dosing through Simulation.

2022

e0237721

2022 Apr 28

1098-6596

<p>Extended interval dosing of tobramycin is recommended for treatment of pulmonary exacerbations in adults and older children with cystic fibrosis (CF), but data are limited in patients less than 5 years of age. We performed a retrospective population pharmacokinetic (PK) analysis of hospitalized children with CF &lt;5 years of age prescribed intravenous tobramycin for a pulmonary exacerbation from March 2011 to September 2018 at our hospital. Children with normal renal function who had ≥1 tobramycin concentration available were included. Nonlinear mixed effects population PK modeling was performed using NONMEM using data from the first 48 h of tobramycin treatment. Monte Carlo simulations were implemented to determine the fraction of simulated patients that met published therapeutic targets with regimens of 10-15 mg/kg/day once-daily dosing. Fifty-eight patients received 111 tobramycin courses (range 1-9/patient). A two-compartment model best described the data. Age, glomerular filtration rate, and vancomycin coadministration were significant covariates on tobramycin clearance. The typical values of clearance and central volume of distribution were 0.252 L/hr/kg^0.75 and 0.308 L/kg, respectively. No once-daily regimens achieved all pre-specified targets simultaneously in &gt;75% of simulated subjects. A dosage of 13 mg/kg/dose best met the predefined targets of C &gt;25 mg/L and AUC of 80-120 mg·h/L. Based on our population PK analysis and simulations, once-daily dosing of tobramycin would not achieve all therapeutic goals in young patients with CF. However, extended-interval dosing regimens may attain therapeutic targets in the majority of young patients.</p>

10.1128/aac.02377-21

Antimicrob Agents Chemother

35481751

Development, validation, and implementation of an UHPLC-MS/MS method for the quantitation of furosemide in infant urine samples.

2022

e5262

2022 Mar

1099-0801

<p>Furosemide is a diuretic drug used to increase urine flow in order to reduce the amount of salt and water in the body. It is commonly utilized to treat preterm infants with chronic lung disease of prematurity. There is a need for a simple and reliable quantitation of furosemide in human urine. We have developed and validated an ultra-high performance liquid chromatography-tandem mass spectrometry method for furosemide quantitation in human urine with an assay range of 0.100-50.0&nbsp;μg/ml. Sample preparation involved solid-phase extraction with 10&nbsp;μl of urine. Intra-day accuracies and precisions for the quality control samples were 94.5-106 and 1.86-10.2%, respectively, while inter-day accuracies and precision were 99.2-102 and 3.38-7.41%, respectively. Recovery for furosemide had an average of 23.8%, with an average matrix effect of 101%. Furosemide was stable in human urine under the assay conditions. Stability for furosemide was shown at 1&nbsp;week (room temperature, 4, -20 and -78°C), 6&nbsp;months (-78°C), and through three freeze-thaw cycles. This robust assay demonstrates accurate and precise quantitation of furosemide in a small volume (10&nbsp;μl) of human urine. It is currently being implemented in an ongoing pediatric clinical study.</p>

10.1002/bmc.5262

Biomed Chromatogr

34648199

Association between postmenstrual age and furosemide dosing practices in very preterm infants.

2022

2022 Jan 24

1476-5543

<p><strong>OBJECTIVE: </strong>Furosemide renal clearance is slow after very preterm (VP) birth and increases with postnatal maturation. We compared furosemide dose frequency and total daily dose between postmenstrual age (PMA) groups in VP infants.</p>

<p><strong>STUDY DESIGN: </strong>Observational cohort study of VP infants exposed to a repeated-dose course of furosemide in Pediatrix neonatal intensive care units (NICU) from 1997 to 2016.</p>

<p><strong>RESULTS: </strong>We identified 6565 furosemide courses among 4638 infants. There were no statistically significant differences between PMA groups on the odds of receiving more frequent furosemide dosing. Furosemide courses initiated at &lt;28 weeks PMA were associated with a higher total daily dose than those initiated at a later PMA.</p>

<p><strong>CONCLUSIONS: </strong>Furosemide dosing practices in the NICU are similar across PMA groups, despite maturational changes in drug disposition. Research is needed to identify and test rational dosing strategies across the PMA spectrum for this commonly used but unproven pharmacotherapy.</p>

10.1038/s41372-022-01320-w

J Perinatol

35075306

Comparative Neurological Safety of Fluoroquinolones vs. Therapeutic Alternatives.

2021

2021 Mar 03

1099-1557

<p><strong>BACKGROUND: </strong>Fluoroquinolones, one of the most commonly prescribed antibiotic classes, have been implicated in cases of central nervous system (CNS) and peripheral nervous system (PNS) adverse events, which highlights the need for epidemiologic studies of the neurological safety of fluoroquinolones.</p>

<p><strong>PURPOSE: </strong>To evaluate the safety of fluoroquinolones with regard to risk of diagnosed neurological dysfunction.</p>

<p><strong>METHODS: </strong>We conducted a propensity score-matched inception cohort study using claims data from a commercially insured population (OptumInsight). Our study included adults prescribed an oral fluoroquinolone or comparator antibiotic between January 2004 and September 2015 for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, uncomplicated urinary tract infection, or acute bronchitis. Our outcomes were CNS dysfunction, and four separate but complementary PNS dysfunction outcomes. Cox proportional hazards models were estimated after matching on propensity scores fitted using the variables age, sex, epilepsy, hereditary peripheral neuropathy, renal dysfunction, diabetes, gabapentinoid use, statin use, isoniazid use, and chemotherapy use.</p>

<p><strong>RESULTS: </strong>Our cohort contained 976,568 individuals exposed to a fluoroquinolone antibiotic matched 1:1 with a comparator. Matching produced balance (standardized mean difference &lt; 0.1) on all variables included in the propensity score. The hazard ratio associated with fluoroquinolone exposure was 1.08 (95% confidence interval 1.05-1.11) for CNS dysfunction, and 1.09 (95% CI 1.07-1.11) for the most commonly occurring PNS dysfunction outcome.</p>

<p><strong>CONCLUSIONS: </strong>Fluoroquinolone antibiotic use was associated with the development of neurological dysfunction versus comparator antibiotic use in the adult population.</p>

10.1002/pds.5219

Pharmacoepidemiol Drug Saf

33655544

Microsampling Assays for Pharmacokinetic Analysis and Therapeutic Drug Monitoring of Antimicrobial Drugs in Children: A Critical Review.

2020

2020 Dec 03

1536-3694

<p><strong>PURPOSE: </strong>With the increasing prevalence of multi-drug resistant organisms, therapeutic drug monitoring (TDM) has become a common tool for assuring the safety and efficacy of antimicrobial drugs at higher doses. Microsampling techniques, including dried blood spotting (DBS) and volumetric absorptive microsampling (VAMS), are attractive tools for TDM and pediatric clinical research. For microsampling techniques to be a useful tool for TDM, it is necessary to establish the blood-plasma correlation and the therapeutic window of antimicrobial drugs in the blood.</p>

<p><strong>METHODS: </strong>DBS involves the collection of small volumes of blood (30 - 50 µL per spot) on a filter paper, while VAMS allows the accurate and precise collection of a fixed volume of blood (10-30 µL) with microsampling devices. One of the major advantages of VAMS is that it reduces or eliminates the volumetric blood hematocrit (HCT) bias associated with DBS. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) is a powerful tool for the accurate quantification of antimicrobial drugs from small volumes of blood specimens.</p>

<p><strong>RESULTS: </strong>This review summarizes the recent LC-MS/MS assays that have employed DBS and VAMS approaches for quantifying antimicrobial drugs. Sample collection, extraction, validation outcomes, including the inter- and intra-assay accuracy and precision, recovery, stability, and matrix effect, as well as the clinical application of these assays and their potential as tools of TDM are discussed herein.</p>

<p><strong>CONCLUSION: </strong>Microsampling techniques, such as VAMS, provide an alternative approach to traditional plasma sample collection for TDM.</p>

10.1097/FTD.0000000000000845

Ther Drug Monit

33278241

A whole blood microsampling assay for vancomycin: development, validation and application for pediatric clinical study.

2020

1295-1310

2020 Sep

1757-6199

<p>Vancomycin is a commonly used antibiotic, which requires therapeutic drug monitoring to ensure optimal treatment. Microsampling assays are attractive tools for pediatric clinical research and therapeutic drug monitoring. A LC-MS/MS&nbsp;method for the quantification of vancomycin in human whole blood employing volumetric absorptive microsampling (VAMS) devices (20&nbsp;μl) was developed and validated. Vancomycin was stable in human whole blood VAMS under assay conditions. Stability for vancomycin was established for at least 160&nbsp;days as dried microsamples at -78°C. This method is currently being utilized for the quantitation of vancomycin in whole blood VAMS for an ongoing pediatric clinical study and representative clinical data are reported.</p>

10.4155/bio-2020-0112

32945688

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

2020

2020 Sep 15

1536-3694

<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>

10.1097/FTD.0000000000000796

Ther Drug Monit

32947559

Lack of synergistic nephrotoxicity between vancomycin and piperacillin/tazobactam in a rat model and a confirmatory cellular model.

2020

2020 Feb 03

1460-2091

<p><strong>BACKGROUND: </strong>Vancomycin and piperacillin/tazobactam are reported in clinical studies to increase acute kidney injury (AKI). However, no clinical study has demonstrated synergistic toxicity, only that serum creatinine increases.</p>

<p><strong>OBJECTIVES: </strong>To clarify the potential for synergistic toxicity between vancomycin, piperacillin/tazobactam and vancomycin + piperacillin/tazobactam treatments by quantifying kidney injury in a translational rat model of AKI and using cell studies.</p>

<p><strong>METHODS: </strong>(i) Male Sprague-Dawley rats (n = 32) received saline, vancomycin 150 mg/kg/day intravenously, piperacillin/tazobactam 1400 mg/kg/day intraperitoneally or vancomycin + piperacillin/tazobactam for 3 days. Urinary biomarkers and histopathology were analysed. (ii) Cellular injury was assessed in NRK-52E cells using alamarBlue®.</p>

<p><strong>RESULTS: </strong>Urinary output increased from Day -1 to Day 1 with vancomycin but only after Day 2 for vancomycin + piperacillin/tazobactam-treated rats. Plasma creatinine was elevated from baseline with vancomycin by Day 2 and only by Day 4 for vancomycin + piperacillin/tazobactam. Urinary KIM-1 and clusterin were increased with vancomycin from Day 1 versus controls (P &lt; 0.001) and only on Day 3 with vancomycin + piperacillin/tazobactam (P &lt; 0.001, KIM-1; P &lt; 0.05, clusterin). The histopathology injury score was elevated only in the vancomycin group when compared with piperacillin/tazobactam as a control (P = 0.04) and generally not so with vancomycin + piperacillin/tazobactam. In NRK-52E cells, vancomycin induced cell death with high doses (IC50 48.76 mg/mL) but piperacillin/tazobactam did not, and vancomycin + piperacillin/tazobactam was similar to vancomycin.</p>

<p><strong>CONCLUSIONS: </strong>All groups treated with vancomycin demonstrated AKI; however, vancomycin + piperacillin/tazobactam was not worse than vancomycin. Histopathology suggested that piperacillin/tazobactam did not worsen vancomycin-induced AKI and may even be protective.</p>

10.1093/jac/dkz563

J. Antimicrob. Chemother.

32011685

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.

2020

113002

2020 Feb 05

1873-264X

<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>

10.1016/j.jpba.2019.113002

J Pharm Biomed Anal

31785929

Mechanisms of antimicrobial-induced nephrotoxicity in children.

2019

2019 Aug 01

1460-2091

<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>

10.1093/jac/dkz325

J. Antimicrob. Chemother.

31369087