{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T02:58:07Z","timestamp":1768877887737,"version":"3.49.0"},"reference-count":41,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T00:00:00Z","timestamp":1679270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Novo Nordisk Foundation","award":["NNF19OC0058958"],"award-info":[{"award-number":["NNF19OC0058958"]}]},{"name":"Kirsten and Freddy Johansen Foundation","award":["NNF19OC0058958"],"award-info":[{"award-number":["NNF19OC0058958"]}]},{"name":"Inge and Asker Larsen Foundation","award":["NNF19OC0058958"],"award-info":[{"award-number":["NNF19OC0058958"]}]},{"name":"Fund of 1870","award":["NNF19OC0058958"],"award-info":[{"award-number":["NNF19OC0058958"]}]},{"name":"Carl and Ellen Hertz Foundation","award":["NNF19OC0058958"],"award-info":[{"award-number":["NNF19OC0058958"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Implant-associated osteomyelitis is one of the most feared complications following orthopedic surgery. Although the risk is low, sufficient antibiotic protection of the implant surface is important. The aim of this study was to assess steady-state piperacillin concentrations in the proximity of an orthopedic implant. Time above the minimal inhibitory concentration (fT&gt;MIC) was evaluated for MIC of 8 (low target) and 16 \u03bcg\/mL (high target). Six female pigs received an intravenous bolus infusion of 4 g\/0.5 g piperacillin\/tazobactam over 30 min every 6 h. Steady state was assumed achieved in the third dosing interval (12\u201318 h). Microdialysis catheters were placed in a cannulated screw in the proximal tibial cancellous bone, in cancellous bone next to the screw, and in cancellous bone on the contralateral tibia. Dialysates were collected from time 12 to 18 h and plasma samples were collected as reference. For the low piperacillin target (8 \u00b5g\/mL), comparable mean fT&gt;MIC across all the investigated compartments (mean range: 54\u201374%) was found. For the high target (16 \u00b5g\/mL), fT&gt;MIC was shorter inside the cannulated screw (mean: 16%) than in the cancellous bone next to the screw and plasma (mean range: 49\u201354%), and similar between the two cancellous bone compartments. To reach more aggressive piperacillin fT&gt;MIC targets in relation to the implant, alternative dosing regimens such as continuous infusion may be considered.<\/jats:p>","DOI":"10.3390\/antibiotics12030615","type":"journal-article","created":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T05:46:42Z","timestamp":1679291202000},"page":"615","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Steady-State Piperacillin Concentrations in the Proximity of an Orthopedic Implant: A Microdialysis Porcine Study"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6453-9681","authenticated-orcid":false,"given":"Johanne Gade","family":"Lille\u00f8re","sequence":"first","affiliation":[{"name":"Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark"},{"name":"Aarhus Denmark Microdialysis Research Group (ADMIRE), Aarhus University Hospital, 8200 Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea Ren\u00e9","family":"J\u00f8rgensen","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark"},{"name":"Aarhus Denmark Microdialysis Research Group (ADMIRE), Aarhus University Hospital, 8200 Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4433-5788","authenticated-orcid":false,"given":"Martin Bruun","family":"Knudsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark"},{"name":"Aarhus Denmark Microdialysis Research Group (ADMIRE), Aarhus University Hospital, 8200 Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pelle","family":"Hanberg","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark"},{"name":"Aarhus Denmark Microdialysis Research Group (ADMIRE), Aarhus University Hospital, 8200 Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7219-7071","authenticated-orcid":false,"given":"Kristina","family":"\u00d6brink-Hansen","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark"},{"name":"Department of Infectious Diseases, Internal Medicine, G\u00f8dstrup Hospital, 7400 Herning, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2960-2342","authenticated-orcid":false,"given":"Sara Kousgaard","family":"T\u00f8stesen","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark"},{"name":"Aarhus Denmark Microdialysis Research Group (ADMIRE), Aarhus University Hospital, 8200 Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kjeld","family":"S\u00f8balle","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark"},{"name":"Department of Orthopedic Surgery, Aarhus University Hospital, 8200 Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maiken","family":"Stilling","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark"},{"name":"Aarhus Denmark Microdialysis Research Group (ADMIRE), Aarhus University Hospital, 8200 Aarhus, Denmark"},{"name":"Department of Orthopedic Surgery, Aarhus University Hospital, 8200 Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7215-8323","authenticated-orcid":false,"given":"Mats","family":"Bue","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark"},{"name":"Aarhus Denmark Microdialysis Research Group (ADMIRE), Aarhus University Hospital, 8200 Aarhus, Denmark"},{"name":"Department of Orthopedic Surgery, Aarhus University Hospital, 8200 Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/S0140-6736(14)61798-0","article-title":"Periprosthetic joint infection","volume":"387","author":"Kapadia","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"878257","DOI":"10.3389\/fbioe.2022.878257","article-title":"Recent Advances and Perspective of Nanotechnology-Based Implants for Orthopedic Applications","volume":"10","author":"Chen","year":"2022","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"237","DOI":"10.47102\/annals-acadmedsg.V40N5p237","article-title":"Orthopaedic implant technology: Biomaterials from past to future","volume":"40","author":"Wang","year":"2011","journal-title":"Ann. Acad. Med. Singap."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1056\/NEJMoa1306801","article-title":"Multistate point-prevalence survey of health care-associated infections","volume":"370","author":"Magill","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/s41579-018-0019-y","article-title":"Implant infections: Adhesion, biofilm formation and immune evasion","volume":"16","author":"Arciola","year":"2018","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1056\/NEJMra035415","article-title":"Treatment of Infections Associated with Surgical Implants","volume":"350","author":"Darouiche","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.injury.2016.09.019","article-title":"Infection after fracture fixation: Current surgical and microbiological concepts","volume":"49","author":"Metsemakers","year":"2018","journal-title":"Injury"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1016\/j.biomaterials.2005.11.044","article-title":"The significance of infection related to orthopedic devices and issues of antibiotic resistance","volume":"27","author":"Campoccia","year":"2006","journal-title":"Biomaterials"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S19","DOI":"10.1097\/BOT.0000000000000461","article-title":"Infection in Orthopaedics","volume":"29","author":"Cook","year":"2015","journal-title":"J. Orthop. Trauma"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1080\/000164701317268978","article-title":"Infection of orthopedic implants and the use of antibiotic-loaded bone cements. A review","volume":"72","author":"Neut","year":"2001","journal-title":"Acta Orthop. Scand."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"163","DOI":"10.3109\/17453679009006513","article-title":"Hip arthroplasty infection: Current concepts","volume":"61","author":"Josefsson","year":"1990","journal-title":"Acta Orthop. Scand."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"196515","DOI":"10.1100\/2012\/196515","article-title":"Economic Impact of Infected Total Knee Arthroplasty","volume":"2012","author":"Haenle","year":"2012","journal-title":"Sci. World J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"732.e731","DOI":"10.1016\/j.cmi.2016.05.004","article-title":"Time trends in the aetiology of prosthetic joint infections: A multicentre cohort study","volume":"22","author":"Benito","year":"2016","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Pfang, B.G., Garc\u00eda-Ca\u00f1ete, J., Garc\u00eda-Lasheras, J., Blanco, A., Au\u00f1\u00f3n, \u00c1., Parron-Cambero, R., Mac\u00edas-Valcayo, A., and Esteban, J. (2019). Orthopedic Implant-Associated Infection by Multidrug Resistant Enterobacteriaceae. J. Clin. Med., 8.","DOI":"10.3390\/jcm8020220"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1302\/0301-620X.67B2.3980532","article-title":"Infection in experimental hip arthroplasties","volume":"67","author":"Southwood","year":"1985","journal-title":"J. Bone Jt. Surg.\u2014Ser. B"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1111\/j.1749-6632.1956.tb36626.x","article-title":"Experimental staphylococcal infections in the skin of man","volume":"65","author":"Elek","year":"1956","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"102413","DOI":"10.1016\/j.anaerobe.2021.102413","article-title":"Clinical and microbiological features of anaerobic implant-related infection in 80 patients after orthopedic surgery","volume":"71","author":"Liu","year":"2021","journal-title":"Anaerobe"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1002\/jor.1100140423","article-title":"Influence of bacterial strains on bone infection","volume":"14","author":"Corder","year":"1996","journal-title":"J. Orthop. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.jiac.2015.02.001","article-title":"Applications of the pharmacokinetic\/pharmacodynamic (PK\/PD) analysis of antimicrobial agents","volume":"21","author":"Isla","year":"2015","journal-title":"J. Infect. Chemother."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Petersen, E.K., Hanberg, P., Knudsen, M., T\u00f8stesen, S.K., J\u00f8rgensen, A.R., \u00d6brink-Hansen, K., S\u00f8balle, K., Stilling, M., and Bue, M. (2022). Intermittent Short-Term Infusion vs. Continuous Infusion of Piperacillin: Steady State Concentrations in Porcine Cervical Spine Tissue Evaluated by Microdialysis. Antibiotics, 11.","DOI":"10.3390\/antibiotics11070910"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1586\/14787210.5.3.365","article-title":"Piperacillin\u2013tazobactam: A \u03b2-lactam\/\u03b2-lactamase inhibitor combination","volume":"5","author":"Gin","year":"2007","journal-title":"Expert Rev. Anti-Infect. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/s15010-018-1116-6","article-title":"Beta-lactams in continuous infusion for Gram-negative bacilli osteoarticular infections: An easy method for clinical use","volume":"46","author":"Ribera","year":"2018","journal-title":"Infection"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1179\/joc.2002.14.1.54","article-title":"Penetration of Piperacillin\/Tazobactam (4 g\/500 mg) into Synovial Tissue","volume":"14","author":"Boselli","year":"2002","journal-title":"J. Chemother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3500","DOI":"10.1016\/j.xphs.2021.06.008","article-title":"Evaluation of Benzylpenicillin as an Internal Standard for Measurement of Piperacillin Bone Concentrations via Microdialysis","volume":"110","author":"Knudsen","year":"2021","journal-title":"J. Pharm. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2734","DOI":"10.1016\/j.injury.2022.06.008","article-title":"Concentrations of co-administered vancomycin and meropenem in the internal dead space of a cannulated screw and in cancellous bone adjacent to the screw\u2014Evaluated by microdialysis in a porcine model","volume":"53","author":"Vittrup","year":"2022","journal-title":"Injury"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"T\u00f8stesen, S.K., Stilling, M., Hanberg, P., Thillemann, T.M., Falstie-Jensen, T., T\u00f8ttrup, M., Knudsen, M., Petersen, E.T., and Bue, M. (2022). High Cefuroxime Concentrations and Long Elimination in an Orthopaedic Surgical Deadspace\u2014A Microdialysis Porcine Study. Antibiotics, 11.","DOI":"10.3390\/antibiotics11020208"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1097\/00003086-199908000-00030","article-title":"Nitric oxide mediated vasoreactivity during fracture repair","volume":"365","author":"Corbett","year":"1999","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"311","DOI":"10.4248\/BR201304002","article-title":"Skeletal Blood Flow in Bone Repair and Maintenance","volume":"1","author":"Tomlinson","year":"2013","journal-title":"Bone Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1002\/jor.20943","article-title":"Biofilm dispersal of community-associated methicillin-resistant Staphylococcus aureus on orthopedic implant material","volume":"28","author":"Lauderdale","year":"2010","journal-title":"J. Orthop. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.vetmic.2007.04.016","article-title":"Time course of biofilm formation by Staphylococcus aureus and Staphylococcus epidermidis mastitis isolates","volume":"124","author":"Oliveira","year":"2007","journal-title":"Vet. Microbiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1097\/00003086-199401000-00016","article-title":"Implant Failure and the Immuno-Incompetent Fibro-Inflammatory Zone","volume":"298","author":"Gristina","year":"1994","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.ijantimicag.2012.10.002","article-title":"\u03b2-Lactam therapeutic drug monitoring in the critically ill: Optimising drug exposure in patients with fluctuating renal function and hypoalbuminaemia","volume":"41","author":"Hayashi","year":"2013","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1080\/14787210.2017.1338139","article-title":"Optimizing \u03b2-lactams treatment in critically-ill patients using pharmacokinetics\/pharmacodynamics targets: Are first conventional doses effective?","volume":"15","author":"Delattre","year":"2017","journal-title":"Expert Rev. Anti Infect. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1016\/S0149-2918(02)80021-2","article-title":"Pharmacokinetics and pharmacodynamics of piperacillin\/tazobactam when administered by continuous infusion and intermittent dosing","volume":"24","author":"Burgess","year":"2002","journal-title":"Clin. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1128\/AAC.41.4.721","article-title":"Importance of beta-lactamase inhibitor pharmacokinetics in the pharmacodynamics of inhibitor-drug combinations: Studies with piperacillin-tazobactam and piperacillin-sulbactam","volume":"41","author":"Lister","year":"1997","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1007\/s001340050424","article-title":"Pharmacokinetics of piperacillin and tazobactam in critically ill patients with renal faliure, treated with continuous veno-venous hemofiltration (CVVH)","volume":"23","author":"Mulder","year":"1997","journal-title":"Intensive Care Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"S14","DOI":"10.1007\/BF01745246","article-title":"Pharmacokinetic characteristics of piperacillin\/tazobactam","volume":"20","author":"Kinzig","year":"1994","journal-title":"Intensive Care Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"895","DOI":"10.2165\/00003088-200544090-00002","article-title":"Microdialysis: Current applications in clinical pharmacokinetic studies and its potential role in the future","volume":"44","author":"Joukhadar","year":"2005","journal-title":"Clin. Pharm."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3506","DOI":"10.1007\/s12035-016-9929-8","article-title":"A Review on Microdialysis Calibration Methods: The Theory and Current Related Efforts","volume":"54","author":"Kho","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_40","unstructured":"(2023, February 21). Biorender. Available online: https:\/\/www.biorender.com."},{"key":"ref_41","unstructured":"(2023, February 21). European Committee on Antimicrobial Susceptibility Testing (EUCAST). Available online: https:\/\/mic.eucast.org\/search\/."}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/12\/3\/615\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:59:02Z","timestamp":1760122742000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/12\/3\/615"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,20]]},"references-count":41,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["antibiotics12030615"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics12030615","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,20]]}}}