First name
Athena
Middle name
F
Last name
Zuppa

Title

Bioanalysis of six antibiotics from volumetric microsamples: a new tool for precision dosing in critically ill children.

Year of Publication

2023

Number of Pages

Date Published

11/2023

ISSN Number

1757-6199

Abstract

Volumetric absorptive microsamples (VAMS) can support pharmacokinetic / pharmacodynamic studies. We present the bioanalytical method development for the simultaneous quantification of ampicillin, cefepime, ceftriaxone, meropenem, piperacillin, tazobactam, and vancomycin from VAMS. Optimal extraction, chromatographic, and mass spectrometry conditions were identified. Maximum extraction recoveries included 100 μl of water for rehydration and methanol for protein precipitation. Chromatographic separation used Phenomenex Kinetex Polar C18 column with a mobile phase comprising water/acetonitrile with formic acid and was fully validated. Hematocrit effects were only observed for vancomycin. Samples were stable for 90 days at -80°C except for meropenem, which was stable for 60 days. Multiple antibiotics can be assayed from a single VAMS sample to facilitate pharmacokinetic/pharmacodynamic studies.

DOI

10.4155/bio-2023-0171

Alternate Title

Bioanalysis

PMID

37991215
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No
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Title

Optimizing Vancomycin Therapy in Critically Ill Children: A Population Pharmacokinetics Study to Inform Vancomycin Area under the Curve Estimation Using Novel Biomarkers.

Year of Publication

2023

Number of Pages

Date Published

04/2023

ISSN Number

1999-4923

Abstract

Area under the curve (AUC)-directed vancomycin therapy is recommended, but Bayesian AUC estimation in critically ill children is difficult due to inadequate methods for estimating kidney function. We prospectively enrolled 50 critically ill children receiving IV vancomycin for suspected infection and divided them into model training (n = 30) and testing (n = 20) groups. We performed nonparametric population PK modeling in the training group using Pmetrics, evaluating novel urinary and plasma kidney biomarkers as covariates on vancomycin clearance. In this group, a two-compartment model best described the data. During covariate testing, cystatin C-based estimated glomerular filtration rate (eGFR) and urinary neutrophil gelatinase-associated lipocalin (NGAL; full model) improved model likelihood when included as covariates on clearance. We then used multiple-model optimization to define the optimal sampling times to estimate AUC for each subject in the model testing group and compared the Bayesian posterior AUC to AUC calculated using noncompartmental analysis from all measured concentrations for each subject. Our full model provided accurate and precise estimates of vancomycin AUC (bias 2.3%, imprecision 6.2%). However, AUC prediction was similar when using reduced models with only cystatin C-based eGFR (bias 1.8%, imprecision 7.0%) or creatinine-based eGFR (bias -2.4%, imprecision 6.2%) as covariates on clearance. All three model(s) facilitated accurate and precise estimation of vancomycin AUC in critically ill children.

DOI

10.3390/pharmaceutics15051336

Alternate Title

Pharmaceutics

PMID

37242578
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No
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Title

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.

Year of Publication

2022

Number of Pages

e0237721

Date Published

2022 Apr 28

ISSN Number

1098-6596

Abstract

<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>

DOI

10.1128/aac.02377-21

Alternate Title

Antimicrob Agents Chemother

PMID

35481751
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Title

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

Year of Publication

2022

Number of Pages

e5262

Date Published

2022 Mar

ISSN Number

1099-0801

Abstract

<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>

DOI

10.1002/bmc.5262

Alternate Title

Biomed Chromatogr

PMID

34648199
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Title

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

Year of Publication

2022

Number of Pages

Date Published

2022 Jan 24

ISSN Number

1476-5543

Abstract

<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>

DOI

10.1038/s41372-022-01320-w

Alternate Title

J Perinatol

PMID

35075306
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Title

Comparative Neurological Safety of Fluoroquinolones vs. Therapeutic Alternatives.

Year of Publication

2021

Number of Pages

Date Published

2021 Mar 03

ISSN Number

1099-1557

Abstract

<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>

DOI

10.1002/pds.5219

Alternate Title

Pharmacoepidemiol Drug Saf

PMID

33655544
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Title

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

Year of Publication

2020

Number of Pages

Date Published

2020 Dec 03

ISSN Number

1536-3694

Abstract

<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>

DOI

10.1097/FTD.0000000000000845

Alternate Title

Ther Drug Monit

PMID

33278241
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Title

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

Year of Publication

2020

Number of Pages

1295-1310

Date Published

2020 Sep

ISSN Number

1757-6199

Abstract

<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>

DOI

10.4155/bio-2020-0112

Alternate Title

PMID

32945688
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Title

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

Year of Publication

2020

Number of Pages

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
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Title

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

Year of Publication

2020

Number of Pages

Date Published

2020 Feb 03

ISSN Number

1460-2091

Abstract

<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>

DOI

10.1093/jac/dkz563

Alternate Title

J. Antimicrob. Chemother.

PMID

32011685
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