Gerbert Coen De Waard1,2, Qiaolin Zhao1,2, Dr. E.S. (Wout) Veltman3, Dr P.K. (Koen) Bos3, Dr. J. (Jakob) van Oldenrijk3, Dr. A.E. (Anouk) Muller4,5,6, Dr. T. (Tim) Preijers1,2, Prof. Dr. B.C.P. (Birgit) Koch1,2,4
1Hospital Pharmacy, Erasmus University MC, 2Rotterdam Clinical Pharmacometrics Group, 3Department of Orthopaedics and Sport Medicine, Erasmus University MC, 4Center for Antimicrobial Optimized Treatment Rotterdam, 5Department of Medical Microbiology and Infectious Diseases, Erasmus University MC, 6Department of Medical Microbiology, Haaglanden Medisch Centrum
Objectives: Prosthetic joint infection (PJI) is a common and growing reason for prosthetic joint replacement in patients that underwent total hip or knee arthroplasty (THA/TKA) [1-2]. Treatment of PJI consists of an one- or two-stage revision of the infected joint followed by extensive antibiotic treatment. However, a clear understanding of the pharmacokinetics (PK) of antibiotics at the bone target site is currently lacking. To that end, a cross-sectional, observational study is being performed (ASTERICS) to study the PK of several IV and oral administered antibiotics. This study aims to analyze target site concentrations and unravel the PK of cefuroxime in PJI patients, identify possible covariates and evaluate whether the current prophylactic dosing regimen is adequate. Methods: ASTERICS study The ASTERICS study is ongoing in the Erasmus Medical Center in Rotterdam, The Netherlands, in the departments of hospital pharmacy, orthopaedics, and sports medicine. During the explantation of the infected prosthetic, two samples of plasma, synovial tissue, and bone were taken. Synovial fluid was collected once. Sampling was performed 30-60min. and 90-120min. after starting IV bolus cefuroxime. To analyze these samples different assays were developed and validated by Bahmany et al. [3-5], enabling quantification of antibiotic concentrations in plasma, synovial fluid, synovial tissue, and bone. Model development From literature, a population PK (popPK) model by Gregs et al. [6] was obtained as it resembled the study population. From this model, initial population PK parameter estimates for the plasma model development were obtained. Model development was conducted using NONMEM v7.5 (ICON Development solutions, Ellicott City, MD, USA). Preliminary plasma and bone data were used to develop this model. Age, body mass index (BMI), lean body weight (LBW), estimated glomerular filtration rate (eGFR), blood loss during operation, albumin, sex and the affected joint (knee or hip) were evaluated as covariate relationships. A sampling importance resampling (SIR) was performed using Pearl-speaks-NONMEM (PsN version 5.3.0) to evaluate the uncertainty of the model parameters. Using the final model, Monte Carlo simulations (MCS, n=1000) were conducted to evaluate optimal dosing regimens. Probability of target attainment (PTA) was analyzed using 65% fT>MIC and 90% fT>MIC with epidemiological cut-off (ECOFF) values for S. Aureus (4 mg/L) and K. pneumoniae (8 mg/L) at an estimated surgery duration of 4 hours. Results: A total of 44 plasma samples and 38 bone samples from 25 patients were collected. Two one-compartment models were joined for plasma and bone, respectively, with a priori allometric scaling on volume of distribution for plasma (V1 = 9.01 L/70kg), volume distribution for bone (V2 = 8.61 L/70kg) and clearance (CL = 5.81 L/h/70kg). Estimation of inter-compartmental clearance (Q) did not improve the model and rate constants (k12(10.6 h-1) and k21(49.4 h-1)) were, therefore, used instead. No allometric scaling of these rate constants was applied. Inter-individual variability (IIV) was estimated on CL (25.1%) of the plasma compartment and k21 (83%). After covariate screening, only eGFR on CL normalized to the population median significantly improved the model, decreasing the IIV on CL with 26.4%. The goodness-of-fit plots and visual predictive checks revealed strong concordance between observed and simulated plasma concentrations. MCS showed that a single IV dose of 1500mg cefuroxime before surgery failed to maintain bone concentrations above the ECOFF of 4 mg/L after 4 hours of administration. Intermittent dosing of 1500mg every 6 or 8 hours also did not allow to achieve the ECOFF target. With a dose of 1500mg, the PTA at 4 hours post-administration was less than 75%. Patients with a eGFR >80 mL/min experienced significant faster clearance and required an increased starting dose of 4500mg to achieve a PTA at 4 hours of 75%. To ensure adequacy of the prophylactic dosing regimen for preventing infections during the perioperative period, a continuous dosing regimen of 4500mg/24h after a loading dose of 1500mg is proposed. Conclusions: In this study, a popPK model was developed able to describe the PK of cefuroxime in plasma and target site. eGFR was obtained as a relevant covariate relationship for clearance of cefuroxime in plasma. MCS provided recommendations for dose adjustments, facilitating the first step toward individualized PJI prophylaxis.
1. Springer, B. D., Cahue, S., Etkin, C. D., Lewallen, D. G., & McGrory, B. J. (2017). Infection burden in total hip and knee arthroplasties: an international registry-based perspective. Arthroplasty today, 3(2), 137–140. https://doi.org/10.1016/j.artd.2017.05.003 2. Koch, B. C. P., Zhao, Q., Oosterhoff, M., van Oldenrijk, J., Abdulla, A., de Winter, B. C. M., Bos, K., & Muller, A. E. (2022). The mysteries of target site concentrations of antibiotics in bone and joint infections: what is known? A narrative review. Expert opinion on drug metabolism & toxicology, 18(9), 587–600. https://doi.org/10.1080/17425255.2022.2117607 3. Bahmany, S., Abdulla, A., Ewoldt, T. M. J., Oehlers, P. L., de Winter, B. C. M., & Koch, B. C. P. (2022). High-throughput analysis for the simultaneous quantification of nine beta-lactam antibiotics in human plasma by UPC2-MS/MS: Method development, validation, and clinical application. Journal of pharmaceutical and biomedical analysis, 219, 114904. https://doi.org/10.1016/j.jpba.2022.114904 4. Demir, Z., Bahmany, S., Bethlehem, C., van Oldenrijk, J., Bos, P. K., & Koch, B. C. P. (2021). Quantification of beta-lactam antibiotics cefuroxime and flucloxacillin in human synovial fluid, using ultra-performance convergence chromatography-tandem mass spectrometry. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 1173, 122696. Advance online publication. https://doi.org/10.1016/j.jchromb.2021.122696 5. Bahmany, S., Holst, A., Hoogendoorn, M. H., Oosterhoff, M., van Oldenrijk, J., Bos, P. K., Veltman, E. S., & Koch, B. C. P. (2024). Quantification of cefuroxime and flucloxacillin in synovial tissue and bone using ultra-performance convergence chromatography-tandem mass spectrometry. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 1241, 124169. https://doi.org/10.1016/j.jchromb.2024.124169 6. Gergs, U., Becker, L., Okoniewski, R., Weiss, M., Delank, K. S., & Neumann, J. (2020). Population pharmacokinetics of cefuroxime and uptake into hip and spine bone of patients undergoing orthopaedic surgery. The Journal of pharmacy and pharmacology, 72(3), 364–370. https://doi.org/10.1111/jphp.13214
Reference: PAGE 33 (2025) Abstr 11397 [www.page-meeting.org/?abstract=11397]
Poster: Clinical Applications