Introduction: Monitoring of AUC24 was updated recommendation in the guideline for the therapeutic drug monitoring (TDM) of vancomycin in Chinese pharmacological society published in 2020. Vancomycin pharmacokinetic profiles are diverse and unique in critically ill patients because of the drastic variability of the patients’ physiological parameters, while the study for population pharmacokinetic (PPK) models in Chinese critically ill patients has been rarely reported. The objectives of this study were to construct a PPK model to describe the pharmacokinetic characteristics of vancomycin in critically ill patients and to individualize vancomycin dosing by model-informed Bayesian estimation for maintenance of AUC24 target at 400–650 mg h/L recommended by the 2020 guideline. Methods: Vancomycin with different dosing was administered intravenously over 1 h for critically ill patients, TDM was started at 48 h or 72 h since initiation of vancomycin therapy for patients. Blood samples were collected from patients for trough concentrations or Cmax. Vancomycin concentrations were determined by high-performance liquid chromatography method with ultraviolet detection. PPK model was performed using the nonlinear mixed-effect model (NONMEM®). Individual PK parameters for critically ill patients treated with vancomycin were estimated using a post hoc empirical Bayesian method based on the final PPK model. AUC24 was calculated as the total daily dose divided by the clearance (L/h). Results: The PPK of vancomycin was determined by a one-compartment model with creatinine clearance as fixed effects. The PK estimates in the final model generally agreed with the median estimates and were contained within the 95% CI generated from the bootstrap results, indicating good precision and stability in the final model. The visual predictive check plots showed the adequate predictive performance of the final PK model and supported a good model fit. The model-informed Bayesian estimation was used to predict the AUC24 of critically ill patient by the acquired TDM results, and the dosing adjustment by maintenance of AUC24 at 400–650 mg h/L had made a great therapeutic effect for the case. Conclusion: This study established a PPK model of vancomycin in Chinese critically ill patients, and individualized dosing of vancomycin by model-informed Bayesian estimation to maintain an AUC24 target at 400–650 mg h/L has been successfully applied in clinic. This result supports the continued use of model-informed Bayesian estimation to vancomycin treatment in critically ill patients.

Journal Section:
Antimicrobial Section / Original Paper
Keywords:
Individualized delivery, Vancomycin, Bayesian dosing approach, AUC24 target, Critically ill patients
1.
Perkins HR. Vancomycin and related antibiotics. Pharmacol Ther. 1982;16(2):181–97.
https://doi.org/10.1016/0163-7258(82)90053-5
2.
Jehl F, Gallion C, Thierry RC, Monteil H. Determination of vancomycin in human serum by high-pressure liquid chromatography. Antimicrob Agents Chemother. 1985 Apr;27(4):503–7.
https://doi.org/10.1128/AAC.27.4.503
3.
Kim DJ, Lee DH, Ahn S, Jung J, Kiem S, Kim SW, et al. A new population pharmacokinetic model for vancomycin in patients with variable renal function: therapeutic drug monitoring based on extended covariate model using CKD-EPI estimation. J Clin Pharm Ther. 2019 Oct;44(5):750–9.
https://doi.org/10.1111/jcpt.12995
4.
Crass RL, Dunn R, Hong J, Krop LC, Pai MP. Dosing vancomycin in the super obese: less is more. J Antimicrob Chemother. 2018 Nov;73(11):3081–6.
https://doi.org/10.1093/jac/dky310
5.
He N, Su S, Ye ZK, Du GH, He B, Li DK, et al. Evidence-based guideline for therapeutic drug monitoring of vancomycin: 2020 update by the division of therapeutic drug monitoring, Chinese pharmacological society. Clin Infect Dis. 2020 Nov;71(Suppl 4):S363–71.
https://doi.org/10.1093/cid/ciaa1536
6.
Tkachuk S, Collins K, Ensom MHH. The relationship between vancomycin trough concentrations and AUC/MIC ratios in pediatric patients: a qualitative systematic review. Paediatr Drugs. 2018 Jan;20(2):153–64.
https://doi.org/10.1007/s40272-018-0282-4
7.
Álvarez R, López Cortés LE, Molina J, Cisneros JM, Pachón J. Optimizing the clinical use of vancomycin. Antimicrob Agents Chemother. 2016 Apr;60(5):2601–9.
https://doi.org/10.1128/AAC.03147-14
8.
Jian Y, Lv H, Liu J, Huang Q, Liu Y, Liu Q, et al. Dynamic changes of Staphylococcus aureus susceptibility to vancomycin, teicoplanin, and linezolid in a central teaching hospital in Shanghai, China, 2008-2018. Front Microbiol. 2020 May;11:908.
https://doi.org/10.3389/fmicb.2020.00908
9.
Oda K, Jono H, Nosaka K, Saito H. Reduced nephrotoxicity with vancomycin therapeutic drug monitoring guided by area under the concentration-time curve against a trough 15-20 mug/mL concentration. Int J Antimicrob Agents. 2020 Oct;56(4):106–9.
10.
Chu Y, Luo Y, Ji S, Jiang M, Zhou B. Population pharmacokinetics of vancomycin in Chinese patients with augmented renal clearance. J Infect Public Health. 2020 Jan;13(1):68–74.
https://doi.org/10.1016/j.jiph.2019.06.016
11.
Westra N, Proost JH, Franssen CFM, Wilms EB, van Buren M, Touw DJ. Vancomycin pharmacokinetic model development in patients on intermittent online hemodiafiltration. PLoS One. 2019 May;14(5):e0216801.
https://doi.org/10.1371/journal.pone.0216801
12.
Wang H, Huang L, Wang J, Ni Y, Zhu Z, Gao P, et al. Population pharmacokinetic study of vancomycin in Chinese pediatric patients with hematological malignancies. Pharmacotherapy. 2020 Oct;40(12):1201–9.
https://doi.org/10.1002/phar.2473
13.
Zhang T, Cheng H, Pan ZY, Mi J, Dong YZ, Zhang Y, et al. Desired vancomycin trough concentration to achieve an AUC0-24/MIC400 in Chinese children with complicated infectious diseases. Basic Clin Pharmacol Toxicol. 2020 Jan;126(1):75–85.
https://doi.org/10.1111/bcpt.13303
14.
Le J, Bradley JS, Murray W, Romanowski GL, Tran TT, Nguyen N, et al. Improved vancomycin dosing in children using area under the curve exposure. Pediatr Infect Dis J. 2013 Apr;32(4):e155–163.
https://doi.org/10.1097/INF.0b013e318286378e
15.
Marsot A, Boulamery A, Bruguerolle B, Simon N. Vancomycin: a review of population pharmacokinetic analyses. Clin Pharmacokinet. 2012 Sept;51:1–13.
https://doi.org/10.2165/11596390-000000000-00000
16.
Akunne OO, Mugabo P, Argent AC. Pharmacokinetics of vancomycin in critically ill children: a systematic review. Eur J Drug Metab Pharmacokinet. 2022 Nov;47(1):31–48.
https://doi.org/10.1007/s13318-021-00730-z
17.
Workum J, Kramers C, Kolwijck E, Schouten JA, de Wildt SN, Brüggemann RJ. Nephrotoxicity of concomitant piperacillin/tazobactam and teicoplanin compared with monotherapy. J Antimicrob Chemother. 2021 Jan;76(1):212–9.
https://doi.org/10.1093/jac/dkaa385
18.
Ji XW, Ji SM, He XR, Zhu X, Chen R, Lu W. Influences of renal function descriptors on population pharmacokinetic modeling of vancomycin in Chinese adult patients. Acta Pharmacol Sin. 2018 Feb;39(2):286–93.
https://doi.org/10.1038/aps.2017.57
19.
Fu X, Lin L, Huang L, Guo L. Clinical application of vancomycin population pharmacokinetics model in patients with hematological diseases and neutropenia. Biopharm Drug Dispos. 2021 Nov;42(9):427–34.
https://doi.org/10.1002/bdd.2303
20.
Jaisue S, Pongsakul C, D’Argenio DZ, Sermsappasuk P. Population pharmacokinetic modeling of vancomycin in Thai patients with heterogeneous and unstable renal function. Ther Drug Monit. 2020 Dec;42(6):856–65.
https://doi.org/10.1097/FTD.0000000000000801
21.
Meng L, Wong T, Huang S, Mui E, Nguyen V, Espinosa G, et al. Conversion from vancomycin trough concentration-guided dosing to area under the curve-guided dosing using two sample measurements in adults: implementation at an academic medical center. Pharmacotherapy. 2019 Feb;39(4):433–42.
https://doi.org/10.1002/phar.2234
22.
Olson J, Hersh AL, Sorensen J, Zobell J, Anderson C, Thorell EA. Intravenous vancomycin therapeutic drug monitoring in children: evaluation of a pharmacy-driven protocol and collaborative practice agreement. J Pediatr Infect Dis Soc. 2020 Jul;9(3):334–41.
https://doi.org/10.1093/jpids/piz036
© 2023 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2023
You do not currently have access to this content.