{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T01:16:55Z","timestamp":1789435015728,"version":"build-2803163510"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T00:00:00Z","timestamp":1621555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005825","name":"National Institute of Food and Agriculture","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005825","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Vet. Sci."],"abstract":"<jats:p>\n                    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-\u03b1) and interleukin-1 beta (IL-1\u03b2) 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\n                    <jats:italic>in vitro<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.3389\/fvets.2021.676774","type":"journal-article","created":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T00:34:46Z","timestamp":1621557286000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Evaluation of Intra-Articular Amikacin Administration in an Equine Non-inflammatory Joint Model to Identify Effective Bactericidal Concentrations While Minimizing Cytotoxicity"],"prefix":"10.3389","volume":"8","author":[{"given":"Lynn","family":"Pezzanite","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyndah","family":"Chow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean","family":"Hendrickson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel L.","family":"Gustafson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Russell Moore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Stoneback","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregg M.","family":"Griffenhagen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Piquini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Phillips","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Lunghofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Dow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie R.","family":"Goodrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1016\/S0140-6736(09)61595-6","article-title":"Bacterial septic arthritis in adults","volume":"375","author":"Matthews","year":"2010","journal-title":"Lancet."},{"key":"B2","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1016\/j.cveq.2005.08.001","article-title":"Diagnosis and treatment of septic arthritis","volume":"21","author":"Morton","year":"2005","journal-title":"Vet Clin North Am Equine Pract."},{"key":"B3","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1093\/rheumatology\/40.1.24","article-title":"A prospective 2-year study of 75 patients with adult-onset septic arthritis","volume":"40","author":"Gupta","year":"2001","journal-title":"Rheumatology."},{"key":"B4","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1128\/CMR.00134-14","article-title":"Staphylococcus aureus infections: epidemiology pathophysiology, clinical manifestations, and management","volume":"28","author":"Tong","year":"2015","journal-title":"Clin Microbiol Rev."},{"key":"B5","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1128\/CMR.00111-13","article-title":"Prosthetic joint infection","volume":"27","author":"Tande","year":"2014","journal-title":"Clin Microbiol Rev."},{"key":"B6","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1016\/j.idc.2017.07.013","article-title":"Septic arthritis and prosthetic joint infections in older adults","volume":"31","author":"Nair","year":"2017","journal-title":"Infect Dis Clin North Am."},{"key":"B7","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1136\/ard.58.4.214","article-title":"Clinical features and outcome of septic arthritis in a single UK health district 1982-1991","volume":"58","author":"Weston","year":"1999","journal-title":"Ann Rheum Dis."},{"key":"B8","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1136\/ard.2007.077131","article-title":"Septic arthritis in Iceland 1990-2002: increasing incidence due to iatrogenic infections","volume":"67","author":"Gierrson","year":"2008","journal-title":"Ann Rheum Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1136\/ard.56.8.470","article-title":"Incidence and sources of native and prosthetic joint infection: a community based prospective survey","volume":"56","author":"Kaandorp","year":"1997","journal-title":"Ann Rheum Dis."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1002\/art.23003","article-title":"The importance of the disease process and disease-modifying antirheumatic drug treatment in the development of septic arthritis in patients with rheumatoid arthritis","volume":"57","author":"Edwards","year":"2007","journal-title":"Arthritis Rheum."},{"key":"B11","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1136\/ard.61.3.267","article-title":"No changes in the distribution of organisms responsible for septic arthritis over a 20-year period","volume":"61","author":"Dubost","year":"2002","journal-title":"Ann Rheum Dis"},{"key":"B12","first-page":"437","article-title":"Pharmacokinetics of single dose intra-articular administration of amikacin in the radiocarpal joints of normal horses","volume-title":"Proceedings of the American College of Veterinary Surgeons Meeting, Chicago, Illinois","author":"Sedrish","year":"1994"},{"key":"B13","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1111\/j.1365-2885.1985.tb00944.x","article-title":"Pharmacokinetics of amikacin in the horse following intravenous and intramuscular administration","volume":"8","author":"Orsini","year":"1985","journal-title":"J Vet Pharm Ther."},{"key":"B14","doi-asserted-by":"publisher","first-page":"189","DOI":"10.2746\/042516406776563233","article-title":"Comparison of amikacin concentrations in normal and inflamed joints of horses following intra-articular administration","volume":"38","author":"Taintor","year":"2006","journal-title":"Equine Vet J."},{"key":"B15","first-page":"644","article-title":"Plasma and synovial fluid concentrations of gentamicin in horses after intra-articular administration of buffered and unbuffered gentamicin","volume":"49","author":"Lloyd","year":"1988","journal-title":"Am J Vet Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1111\/j.1532-950X.2003.00559.x","article-title":"Bone gentamicin concentration after intra-articular or regional intravenous perfusion in the horse","volume":"32","author":"Werner","year":"2003","journal-title":"Vet Surg"},{"key":"B17","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.jiph.2015.10.004","article-title":"Are the leading drugs against Staphylococcus aureus really toxic to cartilage?","volume":"9","author":"Dogan","year":"2016","journal-title":"J Infect Public Health"},{"key":"B18","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1097\/00003086-199612000-00027","article-title":"Effect of cefazolin and vancomycin on osteoblasts in vitro","volume":"333","author":"Edin","year":"1996","journal-title":"Clin Orthop Relat Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1302\/0301-620X.98B.36276","article-title":"A direct approach to treatment of infected total knee arthroplasty","volume":"98","author":"Whiteside","year":"2016","journal-title":"Bone Joint J."},{"key":"B20","article-title":"Vancomycin injected in the knee achieved high synovial fluid concentration with a half-life of 3.4 hours","volume-title":"Proceedings, Orthopedic Research Society","author":"Peppers","year":"2011"},{"key":"B21","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1007\/s11999-016-4977-y","article-title":"One-stage revision with catheter infusion of intra-articular antibiotics successfully treats infected THA","volume":"475","author":"Whiteside","year":"2017","journal-title":"Clin Orthop Relat Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1111\/evj.13243","article-title":"Amikacin induces rapid dose-dependent apoptotic cell death in equine chondrocytes and synovial cells in vitro","volume":"52","author":"Pezzanite","year":"2020","journal-title":"Equine Vet J."},{"key":"B23","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1111\/evj.13314","article-title":"Use of in vitro assays to identify antibiotics that are cytotoxic to normal equine chondrocytes and synovial cells","volume":"53","author":"Pezzanite","year":"2020","journal-title":"Equine Vet J."},{"key":"B24","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1097\/BLO.0b013e31811ff866","article-title":"Antibiotics for local delivery systems cause skeletal cell toxicity in vitro","volume":"462","author":"Antoci","year":"2007","journal-title":"Clin Orthop Relat Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1053\/jvet.2000.9141","article-title":"Determination of synovial fluid and serum concentrations, and morphologic effects of intraarticular ceftiofur sodium in horses","volume":"5","author":"Mills","year":"2000","journal-title":"Vet Surg."},{"key":"B26","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1111\/jvp.12048","article-title":"Pharmacokinetics of tobramycin following intravenous, intramuscular, and intra-articular administration in healthy horses","volume":"36","author":"Newman","year":"2013","journal-title":"J Vet Pharmacol Ther."},{"key":"B27","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1111\/j.2042-3306.2012.00637.x","article-title":"Effects of repeated intra-articular administration of amikacin on serum amyloid A, total protein and nucleated cell count in synovial fluid from healthy horses","volume":"43","author":"Sanchez Teran","year":"2012","journal-title":"Equine Vet J Suppl."},{"key":"B28","first-page":"2485","article-title":"Effect of intra-articular gentamicin sulfate on normal equine synovial membrane","volume":"46","author":"Stover","year":"1985","journal-title":"Am J Vet Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"683","DOI":"10.2460\/ajvr.2002.63.683","article-title":"Effects of continuous intra-articular infusion of gentamicin on synovial membrane and articular cartilage in the tarsocrural joint of horses","volume":"63","author":"Lescun","year":"2002","journal-title":"Am J Vet Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"160","DOI":"10.2460\/ajvr.2001.62.160","article-title":"Effects of enrofloxacin and magnesium deficiency on matrix metabolism in equine articular cartilage","volume":"62","author":"Davenport","year":"2001","journal-title":"Am J Vet Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"704","DOI":"10.2460\/ajvr.2001.62.704","article-title":"Effects of enrofloxacin and ciprofloxacin hydrochloride on canine and equine chondrocytes in culture","volume":"62","author":"Egerbacher","year":"2001","journal-title":"Am J Vet Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"861","DOI":"10.2460\/ajvr.69.7.861","article-title":"Effects of triamcinolone acetonide, sodium hyaluronate, amikacin sulfate, and mepivacaine hydrochloride, alone and in combination, on morphology and matrix composition of lipopolysaccharide-challenged and unchallenged equine articular cartilage explants","volume":"69","author":"Bolt","year":"2008","journal-title":"Am J Vet Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1111\/evj.12045","article-title":"The effects of therapeutic concentrations of gentamicin, amikacin, and hyaluronic acid on cultured bone marrow derived equine mesenchymal stem cells","volume":"45","author":"Bohannon","year":"2013","journal-title":"Equine Vet J."},{"key":"B34","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1111\/evj.13015","article-title":"Plasma and synovial fluid concentrations and cartilage toxicity of bupivacaine following intra-articular administration of liposomal formulation to horses","volume":"51","author":"Knych","year":"2019","journal-title":"Equine Vet J."},{"key":"B35","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1186\/s13567-014-0082-y","article-title":"Infection of equine monocyte-derived macrophages with an attenuated equine infectious anemia virus (EIAV) strain induces a strong resistance to the infection by a virulent EIAV strain","volume":"45","author":"Ma","year":"2014","journal-title":"Vet Res."},{"key":"B36","unstructured":"RasbandW\n          Bethesda, MDNational Institutes of HealthImage J, U.S. (1997\u20132018)2018"},{"key":"B37","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1007\/s10928-015-9432-2","article-title":"Simple, automatic noncompartmental analysis: the PKNCA R package","volume":"42","author":"Denney","year":"2015","journal-title":"J Pharmacokinet Pharmacodyn."},{"key":"B38","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1038\/cdd.2016.159","article-title":"CD73 regulates anti-inflammatory signaling between apoptotic cells and endotoxin-conditioned tissue macrophages","volume":"24","author":"Murphy","year":"2017","journal-title":"Cell Death Diff."},{"key":"B39","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/B978-0-7020-2484-9.50006-7","article-title":"Antimicrobial therapy","volume-title":"Equine Clinical Pharmacology","author":"Dowling","year":"2004"},{"key":"B40","first-page":"447","article-title":"Susceptibility of equine bacterial isolates to antimicrobial agents","volume":"46","author":"Adamson","year":"1985","journal-title":"Am J Vet Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1038\/nri2779","article-title":"Phagocyte partnership during the onset and resolution of inflammation","volume":"10","author":"Soehnlein","year":"2010","journal-title":"Nat Rev Immunol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.jevs.2017.07.008","article-title":"Effect of repeated arthrocentesis on cytology of synovial fluid","volume":"57","author":"Rinnovati","year":"2017","journal-title":"J Equine Vet Sci."},{"key":"B43","first-page":"231","article-title":"Comparison between synovial fluid cytology and joint capsule histopathology in horses with chronic osteochondritis dissecans","volume":"25","author":"Nocera","year":"2019","journal-title":"Large Anim Rev."},{"key":"B44","volume-title":"Equine Hematology, Cytology, and Clinical Chemistry","author":"Walton","year":"2020"},{"key":"B45","doi-asserted-by":"publisher","first-page":"2735","DOI":"10.1021\/acs.jproteome.8b00190","article-title":"Synovial fluid metabolites differentiate between septic and non-septic joint pathologies","volume":"17","author":"Anderson","year":"2018","journal-title":"J Proteome Res."},{"key":"B46","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1055\/s-0038-1632990","article-title":"A comparative study of articular cartilage thickness in the stifle of animal species used in human pre-clinical studies compared to articular cartilage thickness in the human knee","volume":"19","author":"Frisbie","year":"2006","journal-title":"Vet Comp Orthop Traumatol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1177\/1947603511406531","article-title":"Equine models of articular cartilage repair","volume":"2","author":"McIlwraith","year":"2011","journal-title":"Cartilage."},{"key":"B48","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1302\/2046-3758.111.2000132","article-title":"The horse as a model of naturally occurring osteoarthritis","volume":"1","author":"McIlwraith","year":"2012","journal-title":"Bone Joint Res."},{"key":"B49","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1089\/ten.teb.2009.0452","article-title":"Animal models for cartilage regeneration and repair","volume":"16","author":"Chu","year":"2010","journal-title":"Tissue Eng Part B Rev."},{"key":"B50","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/j.joca.2016.07.021","article-title":"Lubricin\/proteoglycan 4 increases in both experimental and naturally occurring equine osteoarthritis","volume":"25","author":"Reesink","year":"2017","journal-title":"Osteo Cart."},{"key":"B51","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1111\/j.2042-3306.1997.tb03138.x","article-title":"Effects of triamcinolone acetonide on an in vivo equine osteochondral fragment exercise model","volume":"29","author":"Frisbie","year":"1997","journal-title":"Equine Vet J."},{"key":"B52","doi-asserted-by":"publisher","first-page":"e0221012","DOI":"10.1371\/journal.pone.0221012","article-title":"Equine or porcine synovial fluid as a novel ex vivo model for the study of bacterial free-floating biofilms that form in human joint infections","volume":"14","author":"Gilbertie","year":"2019","journal-title":"PLoS ONE."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1093\/rheumatology\/kel163a","article-title":"BSR & BHPR, BOA, RCGP and BSAC guidelines for management of the hot swollen joint in adults","volume":"45","author":"Coakley","year":"2006","journal-title":"Rheumatology."},{"key":"B54","doi-asserted-by":"publisher","first-page":"613","DOI":"10.2746\/042516403775467225","article-title":"Endoscopic surgery in the treatment of contaminated or infected synovial structures","volume":"35","author":"Wright","year":"2003","journal-title":"Equine Vet J."}],"container-title":["Frontiers in Veterinary Science"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fvets.2021.676774\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T00:35:03Z","timestamp":1621557303000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fvets.2021.676774\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,21]]},"references-count":54,"alternative-id":["10.3389\/fvets.2021.676774"],"URL":"https:\/\/doi.org\/10.3389\/fvets.2021.676774","relation":{},"ISSN":["2297-1769"],"issn-type":[{"value":"2297-1769","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,21]]},"article-number":"676774"}}