Evaluation of Intra-Articular Amikacin Administration in an Equine Non-inflammatory Joint Model to Identify Effective Bactericidal Concentrations While Minimizing Cytotoxicity.
Abstract: 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 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.
Copyright © 2021 Pezzanite, Chow, Hendrickson, Gustafson, Russell Moore, Stoneback, Griffenhagen, Piquini, Phillips, Lunghofer, Dow and Goodrich.
Publication Date: 2021-05-21 PubMed ID: 34095281PubMed Central: PMC8175670DOI: 10.3389/fvets.2021.676774Google Scholar: Lookup
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Summary
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The research paper analyses the effects of different doses of intra-articular amikacin, a type of antibiotic, in a horse joint model to address septic arthritis, a major concern in veterinary and human health exacerbated by rising multidrug-resistant infections.
Study Overview
- The study explored the impacts of three varying dosages of amikacin (500, 125, and 31.25 mg) on immune and cartilage responses in equine tibiotarsal joints.
- Intra-articular (IA) antibiotic administration was used to achieve high local drug concentrations. This is generally considered off-label usage with unclear standard doses.
Data Collection and Analysis
- Synovial fluid (SF) was sampled at multiple intervals across 24 hours, and cell counts and amikacin concentrations were determined through liquid chromatography-mass spectrometry.
- Cytokine concentrations and collagen degradation products were measured through ELISA (enzyme-linked immunosorbent assay) and multiplex immunoassays.
Findings of the Study
- The mean concentration of amikacin in SF was adequate against most common joint pathogens in horses at all examined time points up to 24 hours for all three amikacin doses.
- The inflammatory cytokines TNF-α (tumor necrosis factor-alpha) and IL-1β (interleukin-1 beta) increased in SF with the highest dose of amikacin. However, there was no corresponding increase in SF cell counts.
- Similarly, amikacin injection led to an increase in biomarkers of cartilage type II collagen cleavage, such as C2C and C12C.
- The research also illustrated that chondrocytes and synoviocytes exposed to amikacin led to cell death via apoptosis and were cleaned up by macrophages in a non-inflammatory process known as efferocytosis.
- Dangerously, neutrophils and T cells showed susceptibility to amikacin cytotoxicity at doses typical in clinical settings, possibly leading to a reduction of cellular inflammatory responses in SF.
Conclusion and Recommendations
- The findings suggest that when deciding to use cytotoxic antibiotics like aminoglycosides intra-articularly, potential harms need to be assessed, and lower doses than those generally practiced in equine practice should be considered.
Cite This Article
APA
Pezzanite L, Chow L, Hendrickson D, Gustafson DL, Russell Moore A, Stoneback J, Griffenhagen GM, Piquini G, Phillips J, Lunghofer P, Dow S, Goodrich LR.
(2021).
Evaluation of Intra-Articular Amikacin Administration in an Equine Non-inflammatory Joint Model to Identify Effective Bactericidal Concentrations While Minimizing Cytotoxicity.
Front Vet Sci, 8, 676774.
https://doi.org/10.3389/fvets.2021.676774 Publication
Researcher Affiliations
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
- Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
- Department of Orthopedic Surgery, University of Colorado School of Medicine, Aurora, CO, United States.
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
- Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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