{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T07:48:38Z","timestamp":1781941718598,"version":"3.54.5"},"reference-count":122,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T00:00:00Z","timestamp":1656374400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> Protein binding can diminish the pharmacological effect of beta-lactam antibiotics. Only the free fraction has an antibacterial effect. The aim of this systematic literature review was to give an overview of the current knowledge of protein binding of cephalosporins in human body fluids as well as to describe patient characteristics influencing the level of protein binding.<\/jats:p><jats:p><jats:bold>Method:<\/jats:bold> A systematic literature search was performed in Embase, Medline ALL, Web of Science Core Collection and the Cochrane Central Register of Controlled Trials with the following search terms: \u201cprotein binding,\u201d \u201cbeta-lactam antibiotic,\u201d and \u201cbody fluid.\u201d Only studies were included where protein binding was measured in humans <jats:italic>in vivo<\/jats:italic>.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> The majority of studies reporting protein binding were performed in serum or plasma. Other fluids included pericardial fluid, blister fluid, bronchial secretion, pleural exudate, wound exudate, cerebrospinal fluid, dialysate, and peritoneal fluid. Protein binding differs between diverse cephalosporins and between different patient categories. For cefazolin, ceftriaxone, cefpiramide, and cefonicid a non-linear pattern in protein binding in serum or plasma was described. Several patient characteristics were associated with low serum albumin concentrations and were found to have lower protein binding compared to healthy volunteers. This was for critically ill patients, dialysis patients, and patients undergoing cardiopulmonary bypass during surgery. While mean\/median percentages of protein binding are lower in these patient groups, individual values may vary considerably. Age is not likely to influence protein binding by itself, however limited data suggest that lower protein binding in newborns. Obesity was not correlated with altered protein binding.<\/jats:p><jats:p><jats:bold>Discussion\/Conclusion:<\/jats:bold> Conclusions on protein binding in other body fluids than blood cannot be drawn due to the scarcity of data. In serum and plasma, there is a large variability in protein binding per cephalosporin and between different categories of patients. Several characteristics were identified which lead to a lower protein binding. The finding that some of the cephalosporins display a non-linear pattern of protein binding makes it even more difficult to predict the unbound concentrations in individual patients. Taken all these factors, it is recommended to measure unbound concentrations to optimize antibiotic exposure in individual patients.<\/jats:p><jats:p><jats:bold>Systematic Review Registration:<\/jats:bold> PROSPERO, identifier (CRD42021252776).<\/jats:p>","DOI":"10.3389\/fphar.2022.900551","type":"journal-article","created":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T07:50:41Z","timestamp":1656402641000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":26,"title":["An Overview of the Protein Binding of Cephalosporins in Human Body Fluids: A Systematic Review"],"prefix":"10.3389","volume":"13","author":[{"given":"C.","family":"Jongmans","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. E.","family":"Muller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Van Den Broek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. De Melo","family":"Cruz De Almeida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Van Den Berg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Van Oldenrijk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. K.","family":"Bos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. C. P.","family":"Koch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1007\/s11096-015-0101-8","article-title":"Targeting Cefuroxime Plasma Concentrations during Coronary Artery Bypass Graft Surgery with Cardiopulmonary Bypass","volume":"37","author":"Aalbers","year":"2015","journal-title":"Int. J. Clin. Pharm."},{"key":"B2","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1093\/jac\/dkz463","article-title":"Continuous versus Intermittent Infusion of Cefotaxime in Critically Ill Patients: a Randomized Controlled Trial Comparing Plasma Concentrations","volume":"75","author":"Aardema","year":"2020","journal-title":"J. Antimicrob. Chemother."},{"key":"B3","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1177\/106002808802201104","article-title":"Disposition of Cefonicid in Orthopedic Surgery Patients","volume":"22","author":"Ackerman","year":"1988","journal-title":"Drug Intell. Clin. Pharm."},{"key":"B4","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1358\/mf.2009.31.1.1338413","article-title":"Cefazolin Plasma Protein Binding Saturability during Pregnancy","volume":"31","author":"Allegaert","year":"2009","journal-title":"Methods Find. Exp. Clin. Pharmacol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1097\/FTD.0000000000000675","article-title":"Meropenem, Cefepime, and Piperacillin Protein Binding in Patient Samples","volume":"42","author":"Al-Shaer","year":"2020","journal-title":"Ther. Drug Monit."},{"key":"B6","doi-asserted-by":"publisher","first-page":"e00440","DOI":"10.1002\/prp2.440","article-title":"Effects of Cardiopulmonary Bypass on the Disposition of Cefazolin in Patients Undergoing Cardiothoracic Surgery","volume":"6","author":"Asada","year":"2018","journal-title":"Pharmacol. Res. Perspect."},{"key":"B7","doi-asserted-by":"publisher","first-page":"2773","DOI":"10.1128\/AAC.01409-08","article-title":"Soft-Tissue Penetration of Ceftobiprole in Healthy Volunteers Determined by In Vivo Microdialysis","volume":"53","author":"Barbour","year":"2009","journal-title":"Antimicrob. Agents Chemother."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1208\/s12248-008-9072-1","article-title":"Protein Binding of Antimicrobials: Methods for Quantification and for Investigation of its Impact on Bacterial Killing","volume":"11","author":"Beer","year":"2009","journal-title":"Aaps J."},{"key":"B9","doi-asserted-by":"publisher","first-page":"741","DOI":"10.2165\/00003088-200241100-00004","article-title":"Clinical Role of Protein Binding of Quinolones","volume":"41","author":"Bergogne-B\u00e9r\u00e9zin","year":"2002","journal-title":"Clin. Pharmacokinet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1862","DOI":"10.1128\/aac.47.6.1862-1866.2003","article-title":"Clinical Pharmacokinetics of Cefamandole and Ceftazidime Administered by Continuous Intravenous Infusion","volume":"47","author":"Berkhout","year":"2003","journal-title":"Antimicrob. Agents Chemother."},{"key":"B11","doi-asserted-by":"publisher","first-page":"16981","DOI":"10.1038\/s41598-021-96654-4","article-title":"Excessive Unbound Cefazolin Concentrations in Critically Ill Patients Receiving Veno-Arterial Extracorporeal Membrane Oxygenation (vaECMO): an Observational Study","volume":"11","author":"Booke","year":"2021","journal-title":"Sci. Rep."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1620","DOI":"10.1093\/jac\/dky071","article-title":"Pharmacokinetics and Pharmacodynamic Target Attainment of Ceftriaxone in Adult Severely Ill Sub-saharan African Patients: A Population Pharmacokinetic Modelling Study","volume":"73","author":"Bos","year":"2018","journal-title":"J. Antimicrob. Chemother."},{"key":"B13","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1128\/aac.37.1.54","article-title":"Pharmacokinetics and Protein Binding of Ceftriaxone during Pregnancy","volume":"37","author":"Bourget","year":"1993","journal-title":"Antimicrob. Agents Chemother."},{"key":"B14","doi-asserted-by":"publisher","first-page":"84","DOI":"10.5195\/jmla.2017.111","article-title":"Reviewing Retrieved References for Inclusion in Systematic Reviews Using EndNote","volume":"105","author":"Bramer","year":"2017","journal-title":"J. Med. Libr. Assoc."},{"key":"B15","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.jchromb.2012.09.016","article-title":"A Method for Determining the Free (Unbound) Concentration of Ten Beta-Lactam Antibiotics in Human Plasma Using High Performance Liquid Chromatography with Ultraviolet Detection","volume":"907","author":"Briscoe","year":"2012","journal-title":"J. Chromatogr. B Anal. Technol. Biomed. Life Sci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1093\/jac\/3.6.585","article-title":"Kidney Transport of Cefazolin in Normal and Impaired Renal Function","volume":"3","author":"Brodwall","year":"1977","journal-title":"J. Antimicrob. Chemother."},{"key":"B17","doi-asserted-by":"publisher","first-page":"5209","DOI":"10.1128\/AAC.01051-10","article-title":"Tissue Penetration and Pharmacokinetics of Tigecycline in Diabetic Patients with Chronic Wound Infections Described by Using In Vivo Microdialysis","volume":"54","author":"Bulik","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"B18","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1093\/jac\/23.1.99","article-title":"Pharmacokinetics and Pharmacodynamics of Total and Unbound Cefoxitin and Cefotetan in Healthy Volunteers","volume":"23","author":"Carver","year":"1989","journal-title":"J. Antimicrob. Chemother."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1585","DOI":"10.1128\/aac.31.10.1585","article-title":"Pharmacokinetics of Cefpiramide in Volunteers with Normal or Impaired Renal Function","volume":"31","author":"Conte","year":"1987","journal-title":"Antimicrob. Agents Chemother."},{"key":"B20","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1146\/annurev.me.27.020176.001443","article-title":"Significance of Serum Protein and Tissue Binding of Antimicrobial Agents","volume":"27","author":"Craig","year":"1976","journal-title":"Annu. Rev. Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"S347","DOI":"10.1093\/infdis\/128.supplement_2.s347","article-title":"Pharmacology of Cefazolin and Other Cephalosporins in Patients with Renal Insufficiency","volume":"128","author":"Craig","year":"1973","journal-title":"J. Infect. Dis."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2738","DOI":"10.1128\/AAC.02570-12","article-title":"Microdialysis Study of Cefotaxime Cerebral Distribution in Patients with Acute Brain Injury","volume":"57","author":"Dahyot-Fizelier","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"B23","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1002\/9781119274315.ch3","article-title":"Equilibrium Dialysis, Ultracentrifugation, and Ultrafiltration in LC\u2010MS Bioanalysis","volume-title":"Sample Preparation in LC\u2010MS Bioanalysis","author":"de Boer","year":"2019"},{"key":"B24","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1093\/jac\/dkw496","article-title":"Population Pharmacokinetics of Cefazolin before, during and after Cardiopulmonary Bypass to Optimize Dosing Regimens for Children Undergoing Cardiac Surgery","volume":"72","author":"de Cock","year":"2017","journal-title":"J. Antimicrob. Chemother."},{"key":"B25","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1002\/jps.2600770807","article-title":"Interindividual Changes in Volume of Distribution of Cefazolin in Newborn Infants and its Prediction Based on Physiological Pharmacokinetic Concepts","volume":"77","author":"Deguchi","year":"1988","journal-title":"J. Pharm. Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1016\/j.xphs.2018.03.023","article-title":"Nonlinear Protein Binding: Not what You Think","volume":"107","author":"Deitchman","year":"2018","journal-title":"J. Pharm. Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1038\/clpt.1991.27","article-title":"Pharmacokinetics and Protein Binding of Cefpiramide in Patients with Alcoholic Cirrhosis","volume":"49","author":"Demotes-Mainard","year":"1991","journal-title":"Clin. Pharmacol. Ther."},{"key":"B28","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1111\/j.1365-2125.1994.tb04278.x","article-title":"Cefpiramide Kinetics and Plasma Protein Binding in Cholestasis","volume":"37","author":"Demotes-Mainard","year":"1994","journal-title":"Br. J. Clin. Pharmacol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1159\/000502474","article-title":"Pharmacokinetics of Total and Unbound Cefazolin during Veno-Arterial Extracorporeal Membrane Oxygenation: A Case Report","volume":"64","author":"Dhanani","year":"2019","journal-title":"Chemotherapy"},{"key":"B30","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1128\/aac.27.4.487","article-title":"Intraoperative Ceforanide Pharmacokinetics and Protein Binding","volume":"27","author":"DiPiro","year":"1985","journal-title":"Antimicrob. Agents Chemother."},{"key":"B31","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1016\/j.xphs.2017.09.006","article-title":"Impact of Experimental Variables on the Protein Binding of Tigecycline in Human Plasma as Determined by Ultrafiltration","volume":"107","author":"Dorn","year":"2018","journal-title":"J. Pharm. Sci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.jchromb.2019.04.025","article-title":"Determination of Total or Free Cefazolin and Metronidazole in Human Plasma or Interstitial Fluid by HPLC-UV for Pharmacokinetic Studies in Man","author":"Dorn","year":"2019","journal-title":"J. Chromatogr. B Anal. Technol. Biomed. Life Sci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"5238","DOI":"10.1128\/AAC.05033-11","article-title":"Plasma and Tissue Pharmacokinetics of Cefazolin in Patients Undergoing Elective and Semielective Abdominal Aortic Aneurysm Open Repair Surgery","volume":"55","author":"Douglas","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"B34","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1128\/aac.30.4.565","article-title":"Effect of Saturable Serum Protein Binding on the Pharmacokinetics of Unbound Cefonicid in Humans","volume":"30","author":"Dudley","year":"1986","journal-title":"Antimicrob. Agents Chemother."},{"key":"B35","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1002\/jcph.1503","article-title":"Ceftriaxone Dosing in a Critically Ill Patient with Hypoalbuminemia during Continuous Venous Hemofiltration: Emphasis on Unbound Pharmacokinetics","volume":"60","author":"Ebisch","year":"2020","journal-title":"J. Clin. Pharmacol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1093\/jac\/21.6.787","article-title":"Pharmacokinetics of Cefixime in the Young and Elderly","volume":"21","author":"Faulkner","year":"1988","journal-title":"J. Antimicrob. Chemother."},{"key":"B37","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1128\/aac.9.5.741","article-title":"Cefuroxime: Human Pharmacokinetics","volume":"9","author":"Foord","year":"1976","journal-title":"Antimicrob. Agents Chemother."},{"key":"B38","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1016\/s0002-9378(12)90844-3","article-title":"Differential Protein Binding of Ceftizoxime in Cord versus Maternal Serum","volume":"168","author":"Fortunato","year":"1993","journal-title":"Am. J. Obstet. Gynecol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1248\/bpb.32.1139","article-title":"Pharmacokinetics of Ceftriaxione, a Third-Generation Cephalosporin, in Pediatric Patients","volume":"32","author":"Fukumoto","year":"2009","journal-title":"Biol. Pharm. Bull."},{"key":"B40","first-page":"366","article-title":"Pharmacokinetics of Cefoxitin in Patients Undergoing Hemodialysis","volume":"17","author":"Garcia","year":"","journal-title":"Int. J. Clin. Pharmacol. Biopharm."},{"key":"B41","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1007\/bf00563118","article-title":"Pharmacokinetics of Cefoxitin in Patients with Normal or Impaired Renal Function","volume":"16","author":"Garcia","year":"","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"557","DOI":"10.3390\/antibiotics10050557","article-title":"Pharmacokinetic\/Pharmacodynamic Target Attainment Based on Measured versus Predicted Unbound Ceftriaxone Concentrations in Critically Ill Patients with Pneumonia: An Observational Cohort Study","volume":"10","author":"Gijsen","year":"2021","journal-title":"Antibiot. (Basel)"},{"key":"B43","doi-asserted-by":"publisher","first-page":"e00634","DOI":"10.1128\/AAC.00634-19","article-title":"High-Dose Ceftriaxone for Bacterial Meningitis and Optimization of Administration Scheme Based on Nomogram","volume":"63","author":"Gr\u00e9goire","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"B44","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/s0003-4975(10)61535-4","article-title":"A Comparison of the Penetration Characteristics of Cephapirin and Cephalothin into Right Atrial Appendage, Muscle, Fat, and Pericardial Fluid of Pediatric Patients Undergoing Open-Heart Operation","volume":"31","author":"Green","year":"1981","journal-title":"Ann. Thorac. Surg."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1007\/s40262-021-01035-9","article-title":"Current Ceftriaxone Dose Recommendations Are Adequate for Most Critically Ill Children: Results of a Population Pharmacokinetic Modeling and Simulation Study","volume":"60","author":"Hartman","year":"2021","journal-title":"Clin. Pharmacokinet."},{"key":"B46","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1007\/bf01711224","article-title":"Clearance of Ceftriaxone in Critical Care Patients with Acute Renal Failure","volume":"16","author":"Heinemeyer","year":"1990","journal-title":"Intensive Care Med."},{"key":"B47","doi-asserted-by":"publisher","first-page":"e02099","DOI":"10.1128\/AAC.02099-20","article-title":"Is Once-Daily High-Dose Ceftriaxone Plus Ampicillin an Alternative for Enterococcus faecalis Infective Endocarditis in Outpatient Parenteral Antibiotic Therapy Programs?","volume":"65","author":"Herrera-Hidalgo","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"B48","doi-asserted-by":"publisher","first-page":"2634","DOI":"10.1016\/j.jtcvs.2014.06.064","article-title":"Skeletal Muscle and Plasma Concentrations of Cefazolin during Cardiac Surgery in Infants","volume":"148","author":"Himebauch","year":"2014","journal-title":"J. Thorac. Cardiovasc Surg."},{"key":"B49","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1097\/00007691-200502000-00014","article-title":"The pH Dependency of the Binding of Drugs to Plasma Proteins in Man","volume":"27","author":"Hinderling","year":"2005","journal-title":"Ther. Drug Monit."},{"key":"B50","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/j.ijantimicag.2016.08.019","article-title":"Evaluation of Total Body Weight and Body Mass Index Cut-Offs for Increased Cefazolin Dose for Surgical Prophylaxis","volume":"48","author":"Hites","year":"2016","journal-title":"Int. J. Antimicrob. Agents"},{"key":"B51","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1089\/sur.2014.250","article-title":"Validation of a Dosing Strategy for Cefazolin for Surgery Requiring Cardiopulmonary Bypass","volume":"16","author":"Hollis","year":"2015","journal-title":"Surg. Infect. (Larchmt)"},{"key":"B52","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1016\/j.ijantimicag.2010.01.001","article-title":"Free Concentration and Protein-Binding Ratio of Ceftriaxone in Cerebrospinal Fluid in Paediatric Patients with Purulent Meningitis Caused by Haemophilus Influenzae Type B","volume":"35","author":"Hoshino","year":"2010","journal-title":"Int. J. Antimicrob. Agents"},{"key":"B53","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1016\/j.clinthera.2005.05.004","article-title":"Cefepime and Continuous Renal Replacement Therapy (CRRT): In Vitro Permeability of Two CRRT Membranes and Pharmacokinetics in Four Critically Ill Patients","volume":"27","author":"Isla","year":"2005","journal-title":"Clin. Ther."},{"key":"B54","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1159\/000100864","article-title":"In Vitro AN69 and Polysulphone Membrane Permeability to Ceftazidime and In Vivo Pharmacokinetics during Continuous Renal Replacement Therapies","volume":"53","author":"Isla","year":"2007","journal-title":"Chemotherapy"},{"key":"B55","doi-asserted-by":"publisher","first-page":"2641","DOI":"10.1093\/jac\/dkaa187","article-title":"Optimization of Flucloxacillin Dosing Regimens in Critically Ill Patients Using Population Pharmacokinetic Modelling of Total and Unbound Concentrations","volume":"75","author":"Jager","year":"2020","journal-title":"J. Antimicrob. Chemother."},{"key":"B56","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1128\/aac.36.2.453","article-title":"Pharmacokinetic Disposition and Bactericidal Activities of Cefepime, Ceftazidime, and Cefoperazone in Serum and Blister Fluid","volume":"36","author":"Kalman","year":"1992","journal-title":"Antimicrob. Agents Chemother."},{"key":"B57","doi-asserted-by":"publisher","first-page":"122081","DOI":"10.1016\/j.jchromb.2020.122081","article-title":"An Adapted LC-MS\/MS Method for the Determination of Free Plasma Concentration of Cefoperazone in Children: Age-dependent Protein Binding","volume":"1144","author":"Kan","year":"2020","journal-title":"J. Chromatogr. B Anal. Technol. Biomed. Life Sci."},{"key":"B58","first-page":"e00779","article-title":"Prediction of Unbound Ceftriaxone Concentration in Children: Simple Bioanalysis Method and Basic Mathematical Equation","volume":"65","author":"Kan","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"B59","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1021\/mp800004s","article-title":"Impact of pH on Plasma Protein Binding in Equilibrium Dialysis","volume":"5","author":"Kochansky","year":"2008","journal-title":"Mol. Pharm."},{"key":"B60","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1248\/bpb1978.10.436","article-title":"Comparative Distribution Kinetics of Cefazolin and Tobramycin in Children","volume":"10","author":"Koshida","year":"1987","journal-title":"J. Pharmacobiodyn"},{"key":"B61","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.jpba.2018.09.044","article-title":"Determination of Total and Free Ceftolozane and Tazobactam in Human Plasma and Interstitial Fluid by HPLC-UV","volume":"163","author":"Kratzer","year":"2019","journal-title":"J. Pharm. Biomed. Anal."},{"key":"B62","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1128\/aac.32.3.298","article-title":"Effect of Protein Binding on Serum Bactericidal Activities of Ceftazidime and Cefoperazone in Healthy Volunteers","volume":"32","author":"Lam","year":"1988","journal-title":"Antimicrob. Agents Chemother."},{"key":"B63","doi-asserted-by":"publisher","first-page":"2547","DOI":"10.1093\/jac\/dkw172","article-title":"Hepatic Cyst Penetration of Cefazolin in Patients Receiving Aspiration Sclerotherapy","volume":"71","author":"Lantinga","year":"2016","journal-title":"J. Antimicrob. Chemother."},{"key":"B64","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/clpt.1984.3","article-title":"Age and Ceftriaxone Kinetics","volume":"35","author":"Luderer","year":"1984","journal-title":"Clin. Pharmacol. Ther."},{"key":"B65","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1177\/0267659107080116","article-title":"Tissue and Plasma Concentrations of Cephuroxime during Cardiac Surgery in Cardiopulmonary Bypass - a Microdialysis Study","volume":"22","author":"Mand'\u00e1k","year":"2007","journal-title":"Perfusion"},{"key":"B66","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1007\/BF01960745","article-title":"Pharmacokinetics of Cefradine, Sulfamethoxazole and Trimethoprim and Their Metabolites in a Patient with Peritonitis Undergoing Continuous Ambulatory Peritoneal Dialysis","volume":"9","author":"Martea","year":"1987","journal-title":"Pharm. Weekbl. Sci."},{"key":"B67","doi-asserted-by":"publisher","first-page":"1639","DOI":"10.1128\/aac.44.6.1639-1644.2000","article-title":"Determinants of Ceftazidime Clearance by Continuous Venovenous Hemofiltration and Continuous Venovenous Hemodialysis","volume":"44","author":"Matzke","year":"","journal-title":"Antimicrob. Agents Chemother."},{"key":"B68","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1592\/phco.20.7.635.35170","article-title":"Determinants of Ceftriaxone Clearance by Continuous Venovenous Hemofiltration and Hemodialysis","volume":"20","author":"Matzke","year":"","journal-title":"Pharmacotherapy"},{"key":"B69","doi-asserted-by":"publisher","first-page":"341","DOI":"10.2174\/1574884715666201228115150","article-title":"Liquid Chromatography-Tandem Mass Spectrometry to Monitor Unbound and Total Ceftriaxone in Serum of Critically Ill Patients","volume":"16","author":"Meenks","year":"2021","journal-title":"Curr. Rev. Clin. Exp. Pharmacol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1093\/jac\/11.3.233","article-title":"Effect of Protein Binding on Antibiotic Activity In Vivo","volume":"11","author":"Merrikin","year":"1983","journal-title":"J. Antimicrob. Chemother."},{"key":"B71","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1097\/00000542-200009000-00023","article-title":"Ceftriaxone Pharmacokinetics during Iatrogenic Hydroxyethyl Starch-Induced Hypoalbuminemia: A Model to Explore the Effects of Decreased Protein Binding Capacity on Highly Bound Drugs","volume":"93","author":"Mimoz","year":"2000","journal-title":"Anesthesiology"},{"key":"B72","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1002\/jps.23872","article-title":"Determination of Atypical Nonlinear Plasma\u2212protein-Binding Behavior of Tigecycline Using an In Vitro Microdialysis Technique","volume":"103","author":"Mukker","year":"2014","journal-title":"J. Pharm. Sci."},{"key":"B73","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1128\/AAC.49.1.220-229.2005","article-title":"Pharmacokinetics of Tigecycline after Single and Multiple Doses in Healthy Subjects","volume":"49","author":"Muralidharan","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"B74","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1093\/bja\/aex026","article-title":"Comparative Total and Unbound Pharmacokinetics of Cefazolin Administered by Bolus versus Continuous Infusion in Patients Undergoing Major Surgery: A Randomized Controlled Trial","volume":"118","author":"Naik","year":"2017","journal-title":"Br. J. Anaesth."},{"key":"B75","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1002\/j.1552-4604.1994.tb01980.x","article-title":"Phase I Study of E1077, a Novel Parenteral Cephem Antibiotic","volume":"34","author":"Nakashima","year":"1994","journal-title":"J. Clin. Pharmacol."},{"key":"B76","doi-asserted-by":"publisher","first-page":"236","DOI":"10.18433\/jpps29856","article-title":"Therapeutic Doses of Eltrombopag Do Not Inhibit Hepatic BCRP in Healthy Volunteers: Intravenous Ceftriaxone as a Model","volume":"21","author":"Neves","year":"2018","journal-title":"J. Pharm. Pharm. Sci."},{"key":"B77","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1128\/aac.17.4.595","article-title":"Effect of Protein Binding on the Penetration of Nonmetabolized Cephalosporins into Atrial Appendage and Pericardial Fluids in Open-Heart Surgical Patients","volume":"17","author":"Nightingale","year":"1980","journal-title":"Antimicrob. Agents Chemother."},{"key":"B78","doi-asserted-by":"publisher","first-page":"1953","DOI":"10.1128\/aac.35.10.1953","article-title":"Antibiotic Tissue Penetration and its Relevance: Impact of Tissue Penetration on Infection Response","volume":"35","author":"Nix","year":"1991","journal-title":"Antimicrob. Agents Chemother."},{"key":"B79","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1093\/jac\/17.3.347","article-title":"Pharmacokinetics and Protein Binding of Cefazolin and Cephalothin in Patients with Cirrhosis","volume":"17","author":"Ohashi","year":"1986","journal-title":"J. Antimicrob. Chemother."},{"key":"B80","doi-asserted-by":"publisher","first-page":"e4254","DOI":"10.1002\/bmc.4254","article-title":"Fast and Sensitive HPLC\/UV Method for Cefazolin Quantification in Plasma and Subcutaneous Tissue Microdialysate of Humans and Rodents Applied to Pharmacokinetic Studies in Obese Individuals","volume":"32","author":"Palma","year":"2018","journal-title":"Biomed. Chromatogr."},{"key":"B81","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1002\/bmc.3622","article-title":"Determination of Cefalothin and Cefazolin in Human Plasma, Urine and Peritoneal Dialysate by UHPLC-MS\/MS: Application to a Pilot Pharmacokinetic Study in Humans","volume":"30","author":"Parker","year":"2016","journal-title":"Biomed. Chromatogr."},{"key":"B82","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.3109\/00498258709167406","article-title":"Plasma Protein Binding of Ceftriaxone","volume":"17","author":"Popick","year":"1987","journal-title":"Xenobiotica"},{"key":"B83","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1097\/FTD.0000000000000736","article-title":"Determination of Total and Unbound Meropenem, Imipenem\/Cilastatin, and Cefoperazone\/Sulbactam in Human Plasma: Application for Therapeutic Drug Monitoring in Critically Ill Patients","volume":"42","author":"Rao","year":"2020","journal-title":"Ther. Drug Monit."},{"key":"B84","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1038\/clpt.1984.10","article-title":"Effect of Protein Binding on Cefmenoxime Steady-State Kinetics in Critical Patients","volume":"35","author":"Reitberg","year":"1984","journal-title":"Clin. Pharmacol. Ther."},{"key":"B85","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s40262-012-0018-5","article-title":"The Clinical Relevance of Plasma Protein Binding Changes","volume":"52","author":"Roberts","year":"2013","journal-title":"Clin. Pharmacokinet."},{"key":"B86","doi-asserted-by":"publisher","first-page":"1495","DOI":"10.1093\/jac\/dku564","article-title":"Plasma and Target-Site Subcutaneous Tissue Population Pharmacokinetics and Dosing Simulations of Cefazolin in Post-trauma Critically Ill Patients","volume":"70","author":"Roberts","year":"2015","journal-title":"J. Antimicrob. Chemother."},{"key":"B87","doi-asserted-by":"publisher","first-page":"415","DOI":"10.3747\/pdi.2015.00008","article-title":"Pharmacokinetics of Intraperitoneal Cefalothin and Cefazolin in Patients Being Treated for Peritoneal Dialysis-Associated Peritonitis","volume":"36","author":"Roberts","year":"2016","journal-title":"Perit. Dial. Int."},{"key":"B88","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1089\/wound.2016.0698","article-title":"Wound Penetration of Cefazolin, Ciprofloxacin, Piperacillin, Tazobactam, and Vancomycin during Negative Pressure Wound Therapy","volume":"6","author":"Rowan","year":"2017","journal-title":"Adv. Wound Care (New Rochelle)"},{"key":"B89","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/jac\/26.suppl_a.1","article-title":"Serum Protein Binding and Extravascular Diffusion of Methoxyimino Cephalosporins. Time Courses of Free and Total Concentrations of Cefotaxime and Ceftriaxone in Serum and Pleural Exudate","author":"Scaglione","year":"1990","journal-title":"J. Antimicrob. Chemother."},{"key":"B90","doi-asserted-by":"publisher","first-page":"211","DOI":"10.2165\/00044011-199714030-00008","article-title":"Serum Protein Binding and Extravascular Diffusion of Cefodizime and Ceftriaxone. An In Vivo Study","volume":"14","author":"Scaglione","year":"","journal-title":"Clin. Drug Investig."},{"key":"B91","doi-asserted-by":"publisher","first-page":"2292","DOI":"10.1128\/AAC.41.10.2292","article-title":"Pharmacokinetic Study of Cefodizime and Ceftriaxone in Sera and Bones of Patients Undergoing Hip Arthroplasty","volume":"41","author":"Scaglione","year":"","journal-title":"Antimicrob. Agents Chemother."},{"key":"B92","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1007\/BF00541531","article-title":"Cefodizime Penetration into Skin Suction Blister Fluid Following a Single Intravenous Dose","volume":"30","author":"Sch\u00e4fer-Korting","year":"1986","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"B93","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1097\/FTD.0000000000000827","article-title":"Measurement of Free Plasma Concentrations of Beta-Lactam Antibiotics: An Applicability Study in Intensive Care Unit Patients","volume":"43","author":"Schie\u00dfer","year":"2021","journal-title":"Ther. Drug Monit."},{"key":"B94","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1111\/bcp.12636","article-title":"Protein Binding Characteristics and Pharmacokinetics of Ceftriaxone in Intensive Care Unit Patients","volume":"80","author":"Schleibinger","year":"2015","journal-title":"Br. J. Clin. Pharmacol."},{"key":"B95","doi-asserted-by":"publisher","first-page":"1107","DOI":"10.1002\/jps.21916","article-title":"Significance of Protein Binding in Pharmacokinetics and Pharmacodynamics","volume":"99","author":"Schmidt","year":"2010","journal-title":"J. Pharm. Sci."},{"key":"B96","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1093\/jac\/dkn522","article-title":"Plasma and Peritoneal Concentration Following Continuous Infusion of Cefotaxime in Patients with Secondary Peritonitis","volume":"63","author":"Seguin","year":"2009","journal-title":"J. Antimicrob. Chemother."},{"key":"B97","doi-asserted-by":"publisher","first-page":"3409","DOI":"10.1016\/j.xphs.2016.07.013","article-title":"Role of Divalent Metal Ions in Atypical Nonlinear Plasma Protein Binding Behavior of Tigecycline","volume":"105","author":"Singh","year":"2016","journal-title":"J. Pharm. Sci."},{"key":"B98","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1007\/BF00563560","article-title":"Alterations of Phenytoin Protein Binding with In Vivo Haemodialysis in Dialysis Encephalopathy","volume":"15","author":"Steele","year":"1979","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"B99","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1111\/j.1365-2885.2006.00801.x","article-title":"Pharmacokinetics and Pharmacodynamics of Cefovecin in Dogs","volume":"29","author":"Stegemann","year":"2006","journal-title":"J. Vet. Pharmacol. Ther."},{"key":"B100","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1038\/clpt.1984.210","article-title":"Single-dose Ceftriaxone Kinetics in Liver Insufficiency","volume":"36","author":"Stoeckel","year":"1984","journal-title":"Clin. Pharmacol. Ther."},{"key":"B101","doi-asserted-by":"publisher","first-page":"1360","DOI":"10.1128\/aac.35.7.1360","article-title":"Cefonicid versus Clindamycin Prophylaxis for Head and Neck Surgery in a Randomized, Double-Blind Trial, with Pharmacokinetic Implications","volume":"35","author":"Swanson","year":"1991","journal-title":"Antimicrob. Agents Chemother."},{"key":"B102","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1128\/aac.11.4.698","article-title":"Levels of Carbenicillin, Ticarcillin, Cephalothin, Cefazolin, Cefamandole, Gentamicin, Tobramycin, and Amikacin in Human Serum and Interstitial Fluid","volume":"11","author":"Tan","year":"1977","journal-title":"Antimicrob. Agents Chemother."},{"key":"B103","doi-asserted-by":"publisher","first-page":"144","DOI":"10.2165\/00003088-197803020-00004","article-title":"Diseases and Drug Protein Binding","volume":"3","author":"Tillement","year":"1978","journal-title":"Clin. Pharmacokinet."},{"key":"B104","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1002\/j.1552-4604.1991.tb03767.x","article-title":"Pharmacokinetics of Ceftriaxone in Liver-Transplant Recipients","volume":"31","author":"Toth","year":"1991","journal-title":"J. Clin. Pharmacol."},{"key":"B105","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1128\/aac.33.2.142","article-title":"Effect of Age and Renal Function on Cefonicid Pharmacokinetics","volume":"33","author":"Trang","year":"1989","journal-title":"Antimicrob. Agents Chemother."},{"key":"B106","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1016\/j.ijantimicag.2016.09.021","article-title":"Total and Unbound Ceftriaxone Pharmacokinetics in Critically Ill Australian Indigenous Patients with Severe Sepsis","volume":"48","author":"Tsai","year":"2016","journal-title":"Int. J. Antimicrob. Agents"},{"key":"B107","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1007\/s00228-021-03100-5","article-title":"Once-daily 1 G Ceftriaxone Optimizes Exposure in Patients with Septic Shock and Hypoalbuminemia Receiving Continuous Veno-Venous Hemodiafiltration","volume":"77","author":"Ulldemolins","year":"2021","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"B108","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1007\/BF00542421","article-title":"Dosage Adjustment for Ceftazidime in Patients with Impaired Renal Function","volume":"30","author":"Van Dalen","year":"1986","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"B109","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1007\/s00228-011-1048-x","article-title":"Pharmacokinetics and Protein Binding of Cefazolin in Morbidly Obese Patients","volume":"67","author":"Van Kralingen","year":"2011","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"B110","doi-asserted-by":"publisher","first-page":"e23100","DOI":"10.1002\/jcla.23100","article-title":"Quantification of Total and Unbound Cefuroxime in Plasma by Ultra-performance Liquid Chromatography Tandem Mass Spectrometry in a Cohort of Critically Ill Patients with Hypoalbuminemia and Renal Failure","volume":"34","author":"van Raaij","year":"2020","journal-title":"J. Clin. Lab. Anal."},{"key":"B111","doi-asserted-by":"publisher","first-page":"2565","DOI":"10.1002\/jps.24064","article-title":"Protein-binding Characteristics of Voriconazole Determined by High-Throughput Equilibrium Dialysis","volume":"103","author":"Vanstraelen","year":"2014","journal-title":"J. Pharm. Sci."},{"key":"B112","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1111\/j.1365-2125.2006.02827.x","article-title":"Protein Binding of Cefazolin Is Saturable In Vivo Both between and within Patients","volume":"63","author":"Vella-Brincat","year":"2007","journal-title":"Br. J. Clin. Pharmacol."},{"key":"B113","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1111\/j.1365-2125.1994.tb04260.x","article-title":"The Renal Clearance of Cefuroxime and Ceftazidime and the Effect of Probenecid on Their Tubular Excretion","volume":"37","author":"Verhagen","year":"1994","journal-title":"Br. J. Clin. Pharmacol."},{"key":"B114","doi-asserted-by":"publisher","first-page":"4496","DOI":"10.3390\/ijms22094496","article-title":"Hypoalbuminemia as Surrogate and Culprit of Infections","volume":"22","author":"Wiedermann","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B115","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1016\/j.ijantimicag.2018.11.018","article-title":"Population Pharmacokinetic Modelling of Total and Unbound Flucloxacillin in Non-critically Ill Patients to Devise a Rational Continuous Dosing Regimen","volume":"53","author":"Wilkes","year":"2019","journal-title":"Int. J. Antimicrob. Agents"},{"key":"B116","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1093\/infdis\/142.1.77","article-title":"The Influence of Protein Binding upon Tissue Fluid Levels of Six Beta-Lactam Antibiotics","volume":"142","author":"Wise","year":"1980","journal-title":"J. Infect. Dis."},{"key":"B117","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1093\/jac\/12.2.105","article-title":"Protein Binding of Beta-Lactams: the Effects on Activity and Pharmacology Particularly Tissue Penetration. I","volume":"12","author":"Wise","year":"1983","journal-title":"J. Antimicrob. Chemother."},{"key":"B118","doi-asserted-by":"publisher","first-page":"3087","DOI":"10.1093\/jac\/dky314","article-title":"Therapeutic Drug Monitoring of \u03b2-lactam Antibiotics in the Critically Ill: Direct Measurement of Unbound Drug Concentrations to Achieve Appropriate Drug Exposures","volume":"73","author":"Wong","year":"2018","journal-title":"J. Antimicrob. Chemother."},{"key":"B119","doi-asserted-by":"publisher","first-page":"445","DOI":"10.2165\/00003088-199630060-00003","article-title":"Measurement and Analysis of Unbound Drug Concentrations","volume":"30","author":"Wright","year":"1996","journal-title":"Clin. Pharmacokinet."},{"key":"B120","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1093\/jac\/11.suppl_a.185","article-title":"Pharmacokinetics and Tolerance of Single Intravenous Doses of Cefotetan Disodium in Male Caucasian Volunteers","author":"Yates","year":"1983","journal-title":"J. Antimicrob. Chemother."},{"key":"B121","doi-asserted-by":"publisher","first-page":"S118","DOI":"10.1016\/s0272-6386(98)70174-x","article-title":"Factors Influencing Serum Albumin in Dialysis Patients","volume":"32","author":"Yeun","year":"1998","journal-title":"Am. J. Kidney Dis."},{"key":"B122","doi-asserted-by":"publisher","first-page":"1632","DOI":"10.1093\/jac\/dkx039","article-title":"The Complexity of Minocycline Serum Protein Binding","volume":"72","author":"Zhou","year":"2017","journal-title":"J. Antimicrob. Chemother."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.900551\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T07:50:50Z","timestamp":1656402650000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.900551\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,28]]},"references-count":122,"alternative-id":["10.3389\/fphar.2022.900551"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.900551","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,28]]},"article-number":"900551"}}