{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T21:15:36Z","timestamp":1740172536520,"version":"3.37.3"},"reference-count":19,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T00:00:00Z","timestamp":1732579200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T00:00:00Z","timestamp":1732579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Faculty of Medicine, University Regensburg","award":["Clinical Scientist Program"],"award-info":[{"award-number":["Clinical Scientist Program"]}]},{"DOI":"10.13039\/501100005296","name":"Universit\u00e4tsklinikum Regensburg","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005296","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["ICMx"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Effective antimicrobial therapy is an essential part of intensive care medicine and renal replacement therapy is an important and common intervention which significantly affects the pharmacokinetics of many antimicrobials. This is especially critical for substances with a narrow therapeutic range, creating a dilemma of weighing the risk of toxicity from increased drug exposure against risk of ineffective treatment and promotion of antimicrobial resistance. To address this problem, we investigate a <jats:italic>target-controlled dialysis<\/jats:italic> by in vitro experiments\u00a0\u2014\u00a0a novel technique in which drug is spiked into the dialysis solution to make use of the physicochemical properties of renal replacement therapy for solute transport, with the goal to reduce the risk of inadequate drug exposure.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Five antibiotics (ceftazidime, meropenem, piperacillin\/tazobactam, vancomycin, flucloxacillin) were dialyzed in an in vitro model of continuous veno-venous hemodialysis using 1\u00a0L of bovine serum albumin solution as simulated patient plasma compartment. This was done with and without antibiotics in target concentrations added to the dialysis solution, mimicking three clinically relevant scenarios: (i) target-controlled dialysis in a subject with sub-therapeutic drug levels, (ii) target-controlled dialysis in a subject with supra-therapeutic drug levels, and (iii) traditional dialysis of drugs starting at the target concentration. Drug levels were quantified by high-performance liquid chromatography. Additionally, the stability over 24\u00a0h of all antibiotics in two typical dialysis solutions was assessed.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Our data shows that with target-controlled dialysis, antibiotic concentrations will change in the desired direction towards the target concentration, depending on the patients\u2019 unbound drug levels in relation to the concentration in the dialysis solution. The desired target concentrations can be induced and maintained, regardless of the initial concentration. Furthermore, the stability tests revealed only a minor and clinically irrelevant loss in drug concentration (all &lt; 10.2%) after 12\u00a0h.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>We outlined the mechanistic plausibility and provided experimental evidence of the feasibility of the target-controlled dialysis concept, which could help to maintain therapeutic concentrations of many time-dependent antibiotics in critically ill patients under renal replacement therapy. The required stability in dialysis solutions was shown for a set of important antibiotics. The next step will be the prudent application of this concept to patients in clinical trials.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s40635-024-00696-7","type":"journal-article","created":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T10:18:32Z","timestamp":1732616312000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Target-controlled dialysis for antibiotics (TCD-ABx)"],"prefix":"10.1186","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1985-2102","authenticated-orcid":false,"given":"Alexander","family":"Dejaco","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"Dorn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Constantin","family":"Lier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Fleischmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Kratzer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharina","family":"Habler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Paal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Gruber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johanna","family":"Rosenberger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin G.","family":"Kees","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,11,26]]},"reference":[{"key":"696_CR1","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1186\/s12879-020-4781-x","volume":"20","author":"A Abdulla","year":"2020","unstructured":"Abdulla A, Ewoldt TMJ, Hunfeld NGM et al (2020) The effect of therapeutic drug monitoring of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients: the DOLPHIN trial protocol of a multi-centre randomised controlled trial. BMC Infect Dis 20:57. https:\/\/doi.org\/10.1186\/s12879-020-4781-x","journal-title":"BMC Infect Dis"},{"issue":"5","key":"696_CR2","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.jiac.2015.02.001","volume":"21","author":"E As\u00edn-Prieto","year":"2015","unstructured":"As\u00edn-Prieto E, Rodr\u00edguez-Gasc\u00f3n A, Isla A (2015) Applications of the pharmacokinetic\/pharmacodynamic (PK\/PD) analysis of antimicrobial agents. J Infect Chemother 21(5):319\u2013329. https:\/\/doi.org\/10.1016\/j.jiac.2015.02.001","journal-title":"J Infect Chemother"},{"key":"696_CR3","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.833189","volume":"13","author":"AV Berry","year":"2022","unstructured":"Berry AV, Kuti JL (2022) Pharmacodynamic thresholds for beta-lactam antibiotics: a story of mouse versus man. Front Pharmacol 13:833189. https:\/\/doi.org\/10.3389\/fphar.2022.833189","journal-title":"Front Pharmacol"},{"key":"696_CR4","doi-asserted-by":"publisher","first-page":"S24","DOI":"10.1046\/j.1523-1755.56.s.72.2.x","volume":"56","author":"J B\u00f6hler","year":"1999","unstructured":"B\u00f6hler J, Donauer J, Keller F (1999) Pharmacokinetic principles during continuous renal replacement therapy: drugs and dosage. Kidney Int 56:S24\u2013S28. https:\/\/doi.org\/10.1046\/j.1523-1755.56.s.72.2.x","journal-title":"Kidney Int"},{"issue":"6","key":"696_CR5","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1007\/s11095-020-02832-w","volume":"37","author":"A Broeker","year":"2020","unstructured":"Broeker A, Vossen MG, Thalhammer F et al (2020) An integrated dialysis pharmacometric (IDP) model to evaluate the pharmacokinetics in patients undergoing renal replacement therapy. Pharm Res 37(6):96. https:\/\/doi.org\/10.1007\/s11095-020-02832-w","journal-title":"Pharm Res"},{"issue":"10","key":"696_CR6","doi-asserted-by":"publisher","first-page":"e795","DOI":"10.1016\/S2666-5247(22)00121-5","volume":"3","author":"ZP Bulman","year":"2022","unstructured":"Bulman ZP, Wicha SG, Nielsen EI et al (2022) Research priorities towards precision antibiotic therapy to improve patient care. Lancet Microbe 3(10):e795\u2013e802. https:\/\/doi.org\/10.1016\/S2666-5247(22)00121-5","journal-title":"Lancet Microbe"},{"issue":"9","key":"696_CR7","doi-asserted-by":"publisher","first-page":"1596","DOI":"10.1093\/cid\/ciy790","volume":"68","author":"RL Crass","year":"2019","unstructured":"Crass RL, Rodvold KA, Mueller BA et al (2019) Renal dosing of antibiotics: are we jumping the gun? Clin Infect Dis 68(9):1596\u20131602. https:\/\/doi.org\/10.1093\/cid\/ciy790","journal-title":"Clin Infect Dis"},{"key":"696_CR8","unstructured":"EUCAST (2024) The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 14.0. https:\/\/www.eucast.org\/clinical_breakpoints. Accessed 10 June 2024"},{"issue":"8","key":"696_CR9","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1007\/s00134-023-07154-0","volume":"49","author":"S Greppmair","year":"2023","unstructured":"Greppmair S, Brinkmann A, Roehr A et al (2023) Towards model-informed precision dosing of piperacillin: multicenter systematic external evaluation of pharmacokinetic models in critically ill adults with a focus on Bayesian forecasting. Intensive Care Med 49(8):966\u2013976. https:\/\/doi.org\/10.1007\/s00134-023-07154-0","journal-title":"Intensive Care Med"},{"issue":"3","key":"696_CR10","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1007\/s00134-021-06609-6","volume":"48","author":"S Hagel","year":"2022","unstructured":"Hagel S, Bach F, Brenner T et al (2022) Effect of therapeutic drug monitoring-based dose optimization of piperacillin\/tazobactam on sepsis-related organ dysfunction in patients with sepsis: a randomized controlled trial. Intensive Care Med 48(3):311\u2013321. https:\/\/doi.org\/10.1007\/s00134-021-06609-6","journal-title":"Intensive Care Med"},{"issue":"5","key":"696_CR11","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1592\/phco.29.5.562","volume":"29","author":"BH Heintz","year":"2009","unstructured":"Heintz BH, Matzke GR, Dager WE (2009) Antimicrobial dosing concepts and recommendations for critically ill adult patients receiving continuous renal replacement therapy or intermittent hemodialysis. Pharmacotherapy 29(5):562\u2013577. https:\/\/doi.org\/10.1592\/phco.29.5.562","journal-title":"Pharmacotherapy"},{"issue":"1","key":"696_CR12","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1177\/1060028019865873","volume":"54","author":"BM Hoff","year":"2020","unstructured":"Hoff BM, Maker JH, Dager WE et al (2020) Antibiotic dosing for critically ill adult patients receiving intermittent hemodialysis, prolonged intermittent renal replacement therapy, and continuous renal replacement therapy: an update. Ann Pharmacother 54(1):43\u201355. https:\/\/doi.org\/10.1177\/1060028019865873","journal-title":"Ann Pharmacother"},{"key":"696_CR13","unstructured":"ICH Expert Working Group (2003) ICH topic Q1A (R2) stability testing of new drug substances and products\u2014scientific guideline. https:\/\/www.ema.europa.eu\/en\/ich-q1a-r2-stability-testing-new-drug-substances-drug-products-scientific-guideline. Accessed 14 June 2024"},{"key":"696_CR14","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.jpba.2018.09.044","volume":"163","author":"A Kratzer","year":"2019","unstructured":"Kratzer A, Schie\u00dfer S, Matzneller P et al (2019) Determination of total and free ceftolozane and tazobactam in human plasma and interstitial fluid by HPLC-UV. J Pharm Biomed Anal 163:34\u201338. https:\/\/doi.org\/10.1016\/j.jpba.2018.09.044","journal-title":"J Pharm Biomed Anal"},{"key":"696_CR15","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.jcrc.2021.10.019","volume":"67","author":"A Lee","year":"2022","unstructured":"Lee A, De Waele JJ, Lipman J (2022) Antibiotic dosing in sustained low-efficiency daily dialysis (SLEDD): basic concepts and dosing strategies. J Crit Care 67:104\u2013107. https:\/\/doi.org\/10.1016\/j.jcrc.2021.10.019","journal-title":"J Crit Care"},{"key":"696_CR16","doi-asserted-by":"publisher","DOI":"10.1080\/17576180.2024.2365526","author":"C Lier","year":"2024","unstructured":"Lier C, Dejaco A, Kratzer A et al (2024) Free serum concentrations of antibiotics determined by ultrafiltration: extensive evaluation of experimental variables. Bioanalysis. https:\/\/doi.org\/10.1080\/17576180.2024.2365526","journal-title":"Bioanalysis"},{"issue":"11","key":"696_CR17","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1093\/ajhp\/zxaa036","volume":"77","author":"MJ Rybak","year":"2020","unstructured":"Rybak MJ, Le J, Lodise TP et al (2020) Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: a revised consensus guideline and review by the American society of health-system pharmacists, the infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases pharmacists. Am J Health-Syst Pharm 77(11):835\u2013864. https:\/\/doi.org\/10.1093\/ajhp\/zxaa036","journal-title":"Am J Health-Syst Pharm"},{"issue":"5","key":"696_CR18","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1016\/j.ijantimicag.2016.12.022","volume":"49","author":"AA Udy","year":"2017","unstructured":"Udy AA, Dulhunty JM, Roberts JA et al (2017) Association between augmented renal clearance and clinical outcomes in patients receiving beta-lactam antibiotic therapy by continuous or intermittent infusion: a nested cohort study of the BLING-II randomised, placebo-controlled, clinical trial. Int J Antimicrob Agents 49(5):624\u2013630. https:\/\/doi.org\/10.1016\/j.ijantimicag.2016.12.022","journal-title":"Int J Antimicrob Agents"},{"issue":"3","key":"696_CR19","doi-asserted-by":"publisher","first-page":"446.e1","DOI":"10.1016\/j.cmi.2021.06.039","volume":"28","author":"E Wallenburg","year":"2022","unstructured":"Wallenburg E, Br\u00fcggemann RJM, Roberts JA et al (2022) A meta-analysis of protein binding of flucloxacillin in healthy volunteers and hospitalized patients. Clin Microbiol Infect 28(3):446.e1-446.e7. https:\/\/doi.org\/10.1016\/j.cmi.2021.06.039","journal-title":"Clin Microbiol Infect"}],"container-title":["Intensive Care Medicine Experimental"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40635-024-00696-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40635-024-00696-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40635-024-00696-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T11:05:55Z","timestamp":1732619155000},"score":1,"resource":{"primary":{"URL":"https:\/\/icm-experimental.springeropen.com\/articles\/10.1186\/s40635-024-00696-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,26]]},"references-count":19,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["696"],"URL":"https:\/\/doi.org\/10.1186\/s40635-024-00696-7","relation":{},"ISSN":["2197-425X"],"issn-type":[{"type":"electronic","value":"2197-425X"}],"subject":[],"published":{"date-parts":[[2024,11,26]]},"assertion":[{"value":"5 August 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 November 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 November 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"108"}}