Considering its very short elimination half-life, the approved oxacillin dosage might not be sufficient to maintain the pharmacokinetic/pharmacodynamics (PK/PD) target of time-dependent antibiotics. This study aimed to describe the population pharmacokinetics of oxacillin and to explore the probability of PK/PD target attainment by using various dosing regimens with oxacillin in staphylococcal infections. Both total and unbound oxacillin plasma concentrations retrieved as a part of routine therapeutic drug-monitoring practice were analyzed using nonlinear mixed-effects modeling. Monte Carlo simulations were used to generate the theoretical distribution of unbound oxacillin plasma concentration-time profiles at various dosage regimens. Data from 24 patients treated with oxacillin for staphylococcal infection have been included into the analysis. The volume of distribution of oxacillin in the population was 11.2 L, while the elimination rate constant baseline of 0.73 h-1 increased by 0.3 h-1 with each 1 mL/s/1.73 m2 of the estimated glomerular filtration rate (eGFR). The median value of oxacillin binding to plasma proteins was 86%. The superiority of continuous infusion in achieving target PK/PD values was demonstrated and dosing according to eGFR was proposed. Daily oxacillin doses of 9.5 g, 11 g, or 12.5 g administered by continuous infusion have been shown to be optimal for achieving target PK/PD values in patients with moderate, mild, or normal renal function, respectively.

Department of Anaesthesia and Intensive Care 1st Faculty of Medicine Charles University and General University Hospital Prague 12808 Prague Czech Republic

Department of Applied Pharmacy Faculty of Pharmacy Masaryk University 60177 Brno Czech Republic

Department of Clinical Pharmacy Military University Hospital Prague 16902 Prague Czech Republic

Department of Pharmacology 1st Faculty of Medicine Charles University and General University Hospital Prague 12800 Prague Czech Republic

Laboratory of Pharmacology and Toxicology AGEL Laboratories 74101 Novy Jicin Czech Republic

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Enna S.J., Bylund D.B. XPharm: The Comprehensive Pharmacology Reference. Elsevier; Amsterdam, The Netherlands: 2008. Elsevier Science (Firm)

State Institute for Drug Control of Czech Republic Prostaphylin—Summary of Product Characteristics. [(accessed on 19 September 2022)]. Available online: https://www.sukl.eu/

Larsen J., Raisen C.L., Ba X., Sadgrove N.J., Padilla-Gonzalez G.F., Simmonds M.S.J., Loncaric I., Kerschner H., Apfalter P., Hartl R., et al. Emergence of methicillin resistance predates the clinical use of antibiotics. Nature. 2022;602:135–141. doi: 10.1038/s41586-021-04265-w. PubMed DOI PMC

World Health Organization Antimicrobial Resistance Surveillance in Europe. [(accessed on 22 September 2022)]. Available online: https://www.ecdc.europa.eu/sites/default/files/documents/Joint-WHO-ECDC-AMR-report-2022.pdf.

Thijssen H.H. Analysis of isoxazolyl penicillins and their metabolites in body fluids by high-performance liquid chromatography. J. Chromatogr. 1980;183:339–345. doi: 10.1016/S0378-4347(00)81714-4. PubMed DOI

Schlossberg D.L., Rafik S. Antibiotics Manual: A Guide to Commonly Used Antimicrobials. John Wiley & Sons; Hoboken, NJ, USA: 2017.

Wong G., Briscoe S., McWhinney B., Ally M., Ungerer J., Lipman J., Roberts J.A. Therapeutic drug monitoring of beta-lactam antibiotics in the critically ill: Direct measurement of unbound drug concentrations to achieve appropriate drug exposures. J. Antimicrob. Chemother. 2018;73:3087–3094. doi: 10.1093/jac/dky314. PubMed DOI

Scharf C., Liebchen U., Paal M., Taubert M., Vogeser M., Irlbeck M., Zoller M., Schroeder I. The higher the better? Defining the optimal beta-lactam target for critically ill patients to reach infection resolution and improve outcome. J. Intensive Care. 2020;8:86. doi: 10.1186/s40560-020-00504-w. PubMed DOI PMC

Wilkes S., van Berlo I., Ten Oever J., Jansman F., Ter Heine R. Population pharmacokinetic modelling of total and unbound flucloxacillin in non-critically ill patients to devise a rational continuous dosing regimen. Int. J. Antimicrob. Agents. 2019;53:310–317. doi: 10.1016/j.ijantimicag.2018.11.018. PubMed DOI

Courjon J., Garzaro M., Roger P.M., Ruimy R., Lavrut T., Chelli M., Raynier J.L., Chirio D., Demonchy E., Cabane L., et al. A Population Pharmacokinetic Analysis of Continuous Infusion of Cloxacillin during Staphylococcus aureus Bone and Joint Infections. Antimicrob. Agents Chemother. 2020;64:e01562-20. doi: 10.1128/AAC.01562-20. PubMed DOI PMC

Klein J.O., Sabath L.D., Steinhauer B.W., Finland M. Oxacillin Treatment of Severe Staphylococcal Infections. N. Engl. J. Med. 1963;269:1215–1225. doi: 10.1056/NEJM196312052692301. PubMed DOI

Foster T.J. Antibiotic resistance in Staphylococcus aureus. Current status and future prospects. FEMS Microbiol. Rev. 2017;41:430–449. doi: 10.1093/femsre/fux007. PubMed DOI

Sinnollareddy M.G., Roberts M.S., Lipman J., Roberts J.A. beta-lactam pharmacokinetics and pharmacodynamics in critically ill patients and strategies for dose optimization: A structured review. Clin. Exp. Pharmacol. Physiol. 2012;39:489–496. doi: 10.1111/j.1440-1681.2012.05715.x. PubMed DOI

European Committee on Antimicrobial Susceptibility Testing Breakpoint Tables for Interpretation of MICs and Zone Diameters. [(accessed on 19 September 2022)]. Available online: https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/v_12.0_Breakpoint_Tables.pdf.