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Evaluation of Intra-Articular Amikacin Administration in an Equine Non-inflammatory Joint Model to Identify Effective Bactericidal Concentrations While Minimizing Cytotoxicity

Septic arthritis causes significant morbidity and mortality in veterinary and human clinical practice and is increasingly complicated by multidrug-resistant infections. Intra-articular (IA) antibiotic administration achieves high local drug concentrations but is considered off-label usage, and appro...

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Autores principales: Pezzanite, Lynn, Chow, Lyndah, Hendrickson, Dean, Gustafson, Daniel L., Russell Moore, A, Stoneback, Jason, Griffenhagen, Gregg M., Piquini, Gabriella, Phillips, Jennifer, Lunghofer, Paul, Dow, Steven, Goodrich, Laurie R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175670/
https://www.ncbi.nlm.nih.gov/pubmed/34095281
http://dx.doi.org/10.3389/fvets.2021.676774
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author Pezzanite, Lynn
Chow, Lyndah
Hendrickson, Dean
Gustafson, Daniel L.
Russell Moore, A
Stoneback, Jason
Griffenhagen, Gregg M.
Piquini, Gabriella
Phillips, Jennifer
Lunghofer, Paul
Dow, Steven
Goodrich, Laurie R.
author_facet Pezzanite, Lynn
Chow, Lyndah
Hendrickson, Dean
Gustafson, Daniel L.
Russell Moore, A
Stoneback, Jason
Griffenhagen, Gregg M.
Piquini, Gabriella
Phillips, Jennifer
Lunghofer, Paul
Dow, Steven
Goodrich, Laurie R.
author_sort Pezzanite, Lynn
collection PubMed
description Septic arthritis causes significant morbidity and mortality in veterinary and human clinical practice and is increasingly complicated by multidrug-resistant infections. Intra-articular (IA) antibiotic administration achieves high local drug concentrations but is considered off-label usage, and appropriate doses have not been defined. Using an equine joint model, we investigated the effects of amikacin injected at three different doses (500, 125, and 31.25 mg) on the immune and cartilage responses in tibiotarsal joints. Synovial fluid (SF) was sampled at multiple time points over 24 h, the cell counts determined, and amikacin concentrations measured by liquid chromatography-mass spectrometry. Cytokine concentrations and collagen degradation products in SF were measured by ELISA and multiplex immunoassays. The mean amikacin concentrations in SF were greater than or equal to the minimum inhibitory concentration (MIC) (0.004 mg/ml) for most common equine joint pathogens at all time points tested to 24 h for all three amikacin doses evaluated. The inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) increased significantly in SF in the highest amikacin dose group, despite the fact that increases in SF cell counts were not observed. Similarly, the biomarkers of cartilage type II collagen cleavage (C2C and C12C) were increased in SF following amikacin injection. Mechanistically, we further demonstrated using in vitro studies that chondrocytes and synoviocytes killed by exposure to amikacin underwent apoptotic cell death and were phagocytosed by macrophages in a non-inflammatory process resembling efferocytosis. Neutrophils and T cells were susceptible to amikacin cytotoxicity at clinically relevant doses, which may result in blunting of cellular inflammatory responses in SF and account for the lack of increase in total nucleated cell counts following amikacin injection. In summary, decisions on whether to inject cytotoxic antibiotics such as aminoglycosides intra-articularly and what doses to use should take into account the potential harm that antibiotics may cause and consider lower doses than those previously reported in equine practice.
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spelling pubmed-81756702021-06-05 Evaluation of Intra-Articular Amikacin Administration in an Equine Non-inflammatory Joint Model to Identify Effective Bactericidal Concentrations While Minimizing Cytotoxicity Pezzanite, Lynn Chow, Lyndah Hendrickson, Dean Gustafson, Daniel L. Russell Moore, A Stoneback, Jason Griffenhagen, Gregg M. Piquini, Gabriella Phillips, Jennifer Lunghofer, Paul Dow, Steven Goodrich, Laurie R. Front Vet Sci Veterinary Science Septic arthritis causes significant morbidity and mortality in veterinary and human clinical practice and is increasingly complicated by multidrug-resistant infections. Intra-articular (IA) antibiotic administration achieves high local drug concentrations but is considered off-label usage, and appropriate doses have not been defined. Using an equine joint model, we investigated the effects of amikacin injected at three different doses (500, 125, and 31.25 mg) on the immune and cartilage responses in tibiotarsal joints. Synovial fluid (SF) was sampled at multiple time points over 24 h, the cell counts determined, and amikacin concentrations measured by liquid chromatography-mass spectrometry. Cytokine concentrations and collagen degradation products in SF were measured by ELISA and multiplex immunoassays. The mean amikacin concentrations in SF were greater than or equal to the minimum inhibitory concentration (MIC) (0.004 mg/ml) for most common equine joint pathogens at all time points tested to 24 h for all three amikacin doses evaluated. The inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) increased significantly in SF in the highest amikacin dose group, despite the fact that increases in SF cell counts were not observed. Similarly, the biomarkers of cartilage type II collagen cleavage (C2C and C12C) were increased in SF following amikacin injection. Mechanistically, we further demonstrated using in vitro studies that chondrocytes and synoviocytes killed by exposure to amikacin underwent apoptotic cell death and were phagocytosed by macrophages in a non-inflammatory process resembling efferocytosis. Neutrophils and T cells were susceptible to amikacin cytotoxicity at clinically relevant doses, which may result in blunting of cellular inflammatory responses in SF and account for the lack of increase in total nucleated cell counts following amikacin injection. In summary, decisions on whether to inject cytotoxic antibiotics such as aminoglycosides intra-articularly and what doses to use should take into account the potential harm that antibiotics may cause and consider lower doses than those previously reported in equine practice. Frontiers Media S.A. 2021-05-21 /pmc/articles/PMC8175670/ /pubmed/34095281 http://dx.doi.org/10.3389/fvets.2021.676774 Text en Copyright © 2021 Pezzanite, Chow, Hendrickson, Gustafson, Russell Moore, Stoneback, Griffenhagen, Piquini, Phillips, Lunghofer, Dow and Goodrich. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Veterinary Science
Pezzanite, Lynn
Chow, Lyndah
Hendrickson, Dean
Gustafson, Daniel L.
Russell Moore, A
Stoneback, Jason
Griffenhagen, Gregg M.
Piquini, Gabriella
Phillips, Jennifer
Lunghofer, Paul
Dow, Steven
Goodrich, Laurie R.
Evaluation of Intra-Articular Amikacin Administration in an Equine Non-inflammatory Joint Model to Identify Effective Bactericidal Concentrations While Minimizing Cytotoxicity
title Evaluation of Intra-Articular Amikacin Administration in an Equine Non-inflammatory Joint Model to Identify Effective Bactericidal Concentrations While Minimizing Cytotoxicity
title_full Evaluation of Intra-Articular Amikacin Administration in an Equine Non-inflammatory Joint Model to Identify Effective Bactericidal Concentrations While Minimizing Cytotoxicity
title_fullStr Evaluation of Intra-Articular Amikacin Administration in an Equine Non-inflammatory Joint Model to Identify Effective Bactericidal Concentrations While Minimizing Cytotoxicity
title_full_unstemmed Evaluation of Intra-Articular Amikacin Administration in an Equine Non-inflammatory Joint Model to Identify Effective Bactericidal Concentrations While Minimizing Cytotoxicity
title_short Evaluation of Intra-Articular Amikacin Administration in an Equine Non-inflammatory Joint Model to Identify Effective Bactericidal Concentrations While Minimizing Cytotoxicity
title_sort evaluation of intra-articular amikacin administration in an equine non-inflammatory joint model to identify effective bactericidal concentrations while minimizing cytotoxicity
topic Veterinary Science
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175670/
https://www.ncbi.nlm.nih.gov/pubmed/34095281
http://dx.doi.org/10.3389/fvets.2021.676774
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