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      Iohexol-measured glomerular filtration rate and urinary biomarker changes between vancomycin and vancomycin plus piperacillin-tazobactam in a translational rat model

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          Abstract

          Recent clinical studies have reported additive nephrotoxicity with the combination of vancomycin and piperacillin-tazobactam. However, preclinical models have failed to replicate this finding. This study assessed differences in iohexol-measured glomerular filtration rate (GFR) and urinary injury biomarkers among rats receiving this antibiotic combination.

          Male Sprague-Dawley rats received either intravenous vancomycin, intraperitoneal piperacillin-tazobactam, or both for 96 hours. Iohexol-measured GFR was used to quantify real-time kidney function changes. Kidney injury was evaluated via the urinary biomarkers: kidney injury molecule-1 (KIM-1), clusterin, and osteopontin.

          Compared to the control, rats that received vancomycin had numerically lower GFR after drug dosing on day 3. Rats in this group also had elevations in urinary KIM-1 on experimental days 2 and 4. Increasing urinary KIM-1 was found to correlate with decreasing GFR on experimental days 1 and 3. Rats that received vancomycin+piperacillin-tazobactam did not exhibit worse kidney function or injury biomarkers compared to vancomycin alone.

          The combination of vancomycin+piperacillin-tazobactam does not cause additive nephrotoxicity in a translational rat model. Future clinical studies investigating this antibiotic combination should employ more sensitive biomarkers of kidney function and injury, similar to those utilized in this study.

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          Most cited references37

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          New Creatinine- and Cystatin C–Based Equations to Estimate GFR without Race

          Current equations for estimated glomerular filtration rate (eGFR) that use serum creatinine or cystatin C incorporate age, sex, and race to estimate measured GFR. However, race in eGFR equations is a social and not a biologic construct.
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            No adjustments are needed for multiple comparisons.

            K Rothman (1990)
            Adjustments for making multiple comparisons in large bodies of data are recommended to avoid rejecting the null hypothesis too readily. Unfortunately, reducing the type I error for null associations increases the type II error for those associations that are not null. The theoretical basis for advocating a routine adjustment for multiple comparisons is the "universal null hypothesis" that "chance" serves as the first-order explanation for observed phenomena. This hypothesis undermines the basic premises of empirical research, which holds that nature follows regular laws that may be studied through observations. A policy of not making adjustments for multiple comparisons is preferable because it will lead to fewer errors of interpretation when the data under evaluation are not random numbers but actual observations on nature. Furthermore, scientists should not be so reluctant to explore leads that may turn out to be wrong that they penalize themselves by missing possibly important findings.
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              Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study.

              Post hoc analyses of clinical trial data suggested that linezolid may be more effective than vancomycin for treatment of methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. This study prospectively assessed efficacy and safety of linezolid, compared with a dose-optimized vancomycin regimen, for treatment of MRSA nosocomial pneumonia. This was a prospective, double-blind, controlled, multicenter trial involving hospitalized adult patients with hospital-acquired or healthcare-associated MRSA pneumonia. Patients were randomized to receive intravenous linezolid (600 mg every 12 hours) or vancomycin (15 mg/kg every 12 hours) for 7-14 days. Vancomycin dose was adjusted on the basis of trough levels. The primary end point was clinical outcome at end of study (EOS) in evaluable per-protocol (PP) patients. Prespecified secondary end points included response in the modified intent-to-treat (mITT) population at end of treatment (EOT) and EOS and microbiologic response in the PP and mITT populations at EOT and EOS. Survival and safety were also evaluated. Of 1184 patients treated, 448 (linezolid, n = 224; vancomycin, n = 224) were included in the mITT and 348 (linezolid, n = 172; vancomycin, n = 176) in the PP population. In the PP population, 95 (57.6%) of 165 linezolid-treated patients and 81 (46.6%) of 174 vancomycin-treated patients achieved clinical success at EOS (95% confidence interval for difference, 0.5%-21.6%; P = .042). All-cause 60-day mortality was similar (linezolid, 15.7%; vancomycin, 17.0%), as was incidence of adverse events. Nephrotoxicity occurred more frequently with vancomycin (18.2%; linezolid, 8.4%). For the treatment of MRSA nosocomial pneumonia, clinical response at EOS in the PP population was significantly higher with linezolid than with vancomycin, although 60-day mortality was similar.
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                Author and article information

                Journal
                bioRxiv
                BIORXIV
                bioRxiv
                Cold Spring Harbor Laboratory
                12 March 2023
                : 2023.03.09.532007
                Affiliations
                [1 ]Midwestern University- Downers Grove Campus, Department of Pharmacy Practice, Downers Grove, IL, USA
                [2 ]Midwestern University- Downers Grove Campus, Pharmacometrics Center of Excellence, Downers Grove, IL, USA
                [3 ]Northwestern Memorial Hospital, Department of Pharmacy, Chicago, IL, USA
                [4 ]Midwestern University- Downers Grove Campus, Department of Pharmacology, Downers Grove, IL, USA
                [5 ]Midwestern University- Downers Grove Campus, College of Graduate Studies, Downers Grove, IL, USA
                [6 ]Mayo Clinic, Department of Pharmacy, Rochester, MN, USA
                [7 ]Optimal Data Analysis, LLC, Chicago, Illinois, USA
                Author notes

                Author contributions:

                JC had primary responsibility for sample collection, analytical quantification, data analysis, and authored the paper. GP performed all animal surgeries. SM, KV, and EL assisted with care of animals and sample collection. EB assisted with data analysis. MS designed and oversaw experimental conduct, including data analysis. All authors discussed and commented on the manuscript.

                [* ] Corresponding author and reprint requests: Marc H. Scheetz, PharmD, MSc; Professor of Pharmacy Practice and Pharmacology; Midwestern University; 555 31 st St., Downers Grove, IL 60515, Phone: 630-515-6116; Fax: 630-515-6958; mschee@ 123456midwestern.edu
                Article
                10.1101/2023.03.09.532007
                10029007
                36945555
                e98dd1f5-f75c-45c4-9253-eb00b785532b

                This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use.

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                vancomycin,nephrotoxicity,glomerular function,kidney injury biomarkers

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