Meropenem Determination in Human Plasma by LC-MS/MS and Evaluation for Therapeutic Drug Monitoring in ICU Patients

Dita Amalia; Endang Lukitaningsih; Akhmad Kharis Nugroho; Ika Puspitasari

doi:10.24071/jpsc.0011827

Meropenem Determination in Human Plasma by LC-MS/MS and Evaluation for Therapeutic Drug Monitoring in ICU Patients

Dita Amalia⁽¹⁾, Endang Lukitaningsih^(2*), Akhmad Kharis Nugroho⁽³⁾, Ika Puspitasari⁽⁴⁾,

(1) Master in Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Gadjah Mada
(2) Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada
(3) 3Department of Pharmaceutics, Faculty of Pharmacy, Universitas Gadjah Mada
(4) Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada
(*) Corresponding Author

Abstract

Meropenem is a broad-spectrum beta-lactam antibiotic widely used in intensive care units (ICUs) for severe bacterial infections. Therapeutic drug monitoring (TDM) is essential to optimize its dosing, ensuring effective bacterial eradication while minimizing toxicity and resistance.

This study aimed to determine meropenem concentrations in human plasma using LC-MS/MS and evaluate its application in TDM for ICU patients. Meropenem concentrations in plasma samples from ICU patients were analysed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The study included 40 plasma samples from 20 patients receiving meropenem continuous infusion. Validation followed ICH M10 (2022) guidelines, assessing specificity, accuracy, precision, stability, and dilution integrity. The developed LC-MS/MS method demonstrated high selectivity, sensitivity, and linearity (r = 0.9930.996) over the 102000 ng/mL range. Accuracy and precision met ICH M10 acceptance criteria, with %CV <15%. All ICU patients maintained %fT>Minimum Inhibitory Concentration (MIC) >40%, ensuring adequate bacterial eradication. Notably, patients with renal impairment required dose adjustments, while those with high creatinine clearance needed increased dosing. The validated LC-MS/MS method is suitable for meropenem TDM in ICU patients, allowing individualized dosing adjustments to optimize therapy.

Keywords

ICU; LC-MS/MS; Meropenem; Therapeutic Drug Monitoring; Pharmacokinetics

References

Abdul-Aziz, M. H., Alffenaar, J. W. C., Bassetti, M., Bracht, H., Dimopoulos, G., Marriott, D., Neely, M. N., Paiva, J. A., Pea, F., Sjovall, F., Timsit, J. F., Udy, A. A., Wicha, S. G., Zeitlinger, M., De Waele, J. J., & Roberts, J. A. (2020). Antimicrobial therapeutic drug monitoring in critically ill adult patients: a Position Paper#. Intensive Care Medicine, 46(6), 11271153. https://doi.org/10.1007/s00134-020-06050-1

Ahmed, N., Jen, S. P., Altshuler, D., Papadopoulos, J., Pham, V. P., & Dubrovskaya, Y. (2020). Evaluation of Meropenem Extended Versus Intermittent Infusion Dosing Protocol in Critically Ill Patients. Journal of Intensive Care Medicine, 35(8), 763771. https://doi.org/10.1177/0885066618784264

Ai, M. Y., Chang, W. L., & Liu, C. Y. (2024). Mortality of continuous infusion versus intermittent bolus of meropenem: a systematic review and meta-analysis of randomized controlled trials. In Frontiers in Microbiology (Vol. 15). Frontiers Media SA. https://doi.org/10.3389/fmicb.2024.1337570

Anggita, D., Nuraisyah, S., & Wiriansya, E. P. (2022). Mekanisme Kerja Antibiotik Open Access ABSTRAK. In UMI Medical Journal (Vol. 7).

Barone, R., Conti, M., Giorgi, B., Gatti, M., Cojutti, P. G., Viale, P., & Pea, F. (2023). Fast and Sensitive Method for Simultaneous Quantification of Meropenem and Vaborbactam in Human Plasma Microsamples by Liquid ChromatographyTandem Mass Spectrometry for Therapeutic Drug Monitoring. Antibiotics, 12(4). https://doi.org/10.3390/antibiotics12040719

Boonpeng, A., Jaruratanasirikul, S., Jullangkoon, M., Samaeng, M., Wattanavijitkul, T., Bhurayanontachai, R., & Pattharachayakul, S. (2022). Population Pharmacokinetics/Pharmacodynamics and Clinical Outcomes of Meropenem in Critically Ill Patients. Antimicrobial Agents and Chemotherapy, 66(11). https://doi.org/10.1128/aac.00845-22

Cao, H., Jiang, Y., Wang, S., Cao, H., Li, Y., & Huang, J. (2022). Dried Plasma Spot Based LCMS/MS Method for Monitoring of Meropenem in the Blood of Treated Patients. Molecules, 27(6). https://doi.org/10.3390/molecules27061991

CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests. 13th ed. CLSI standard M02. Wayne, PA: Clinical and Laboratory Standards Institute; 2018.

Desjardins, C., Li, Z., & Mcconville, P. (2019). Carryover Mitigation Using Needle Wash Solvent Chemistry And Autosampler Features Of A UPLC-MS System.

European Committee on Antimicrobial Susceptibility Testing (EUCAST). (2023). Breakpoint tables for interpretation of MICs and zone diameters, Version 13.0. Retrieved from https://www.eucast.org (accessed 02.01.25)

Evans, L., Rhodes, A., Alhazzani, W., Antonelli, M., Coopersmith, C. M., French, C., Machado, F. R., Mcintyre, L., Ostermann, M., Prescott, H. C., Schorr, C., Simpson, S., Wiersinga, W. J., Alshamsi, F., Angus, D. C., Arabi, Y., Azevedo, L., Beale, R., Beilman, G., Levy, M. (2021). Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Medicine, 47(11), 11811247. https://doi.org/10.1007/s00134-021-06506-y

Gu, H., Liu, G., Wang, J., Aubry, A. F., & Arnold, M. E. (2014). Selecting the correct weighting factors for linear and quadratic calibration curves with least-squares regression algorithm in bioanalytical LC-MS/MS assays and impacts of using incorrect weighting factors on curve stability, data quality, and assay performance. Analytical Chemistry, 86(18), 89598966. https://doi.org/10.1021/ac5018265

Harmita, K., Harahap, Y., dan Supandi. 2019. Liquid Chromatography-Tandem Mass Spectrometry (LC MS/MS). ISFI, Jakarta.

Helset, E., Cheng, V., Sporsem, H., Thorstensen, C., Nordy, I., Gammelsrud, K. W., Hanssen, G., Ponzi, E., Lipman, J., & von der Lippe, E. (2024b). Meropenem pharmacokinetic/pharmacodynamic target attainment and clinical response in ICU patients: A prospective observational study. Acta Anaesthesiologica Scandinavica, 68(4), 502511. https://doi.org/10.1111/aas.14376

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). (2022). ICH M10: Bioanalytical Method Validation. Retrieved from https://www.ich.org/page/multidisciplinary-guidelines

Kothekar, A. T., Divatia, J. V., Myatra, S. N., Patil, A., Nookala Krishnamurthy, M., Maheshwarappa, H. M., Siddiqui, S. S., Gurjar, M., Biswas, S., & Gota, V. (2020). Clinical pharmacokinetics of 3-h extended infusion of meropenem in adult patients with severe sepsis and septic shock: implications for empirical therapy against Gram-negative bacteria. Annals of Intensive Care, 10(1). https://doi.org/10.1186/s13613-019-0622-8

Letter, William. (2015). Sample Carry-Over (Carryover) Contamination in HPLC & LC-MS Systems. 10.13140/RG.2.1.4607.7283.

Li, L., Sassen, S. D. T., Ewoldt, T. M. J., Abdulla, A., Hunfeld, N. G. M., Muller, A. E., de Winter, B. C. M., Endeman, H., & Koch, B. C. P. (2023). Meropenem Model-Informed Precision Dosing in the Treatment of Critically Ill Patients: Can We Use It? Antibiotics, 12(2). https://doi.org/10.3390/antibiotics12020383

Mattioli, F., Fucile, C., Del Bono, V., Marini, V., Parisini, A., Molin, A., Zuccoli, M. L., Milano, G., Danesi, R., Marchese, A., Polillo, M., Viscoli, C., Pelosi, P., Martelli, A., & Di Paolo, A. (2016). Population pharmacokinetics and probability of target attainment of meropenem in critically ill patients. European Journal of Clinical Pharmacology, 72(7), 839848. https://doi.org/10.1007/s00228-016-2053-x

Minichmayr, I. K., Kappetein, S., Brill, M. J. E., & Friberg, L. E. (2022). Model-Informed Translation of In Vitro Effects of Short-, Prolonged- and Continuous-Infusion Meropenem against Pseudomonas aeruginosa to Clinical Settings. Antibiotics, 11(8). https://doi.org/10.3390/antibiotics11081036

Mller, M., & Gedeon, J. (2017). Sepsis and antibiotics: pharmacokinetics and pharmacodynamics in critically ill patients. Infectious Disease Clinics of North America, 31(4), 467-478.

Oliveira, M. S., Machado, A. S., Mendes, E. T., Chaves, L., Perdigo Neto, L. V., Vieira da Silva, C., Cavani Jorge Santos, S. R., Sanches, C., Macedo, E., & Levin, A. S. (2020). Pharmacokinetic and Pharmacodynamic Characteristics of Vancomycin and Meropenem in Critically Ill Patients Receiving Sustained Low-efficiency Dialysis. Clinical Therapeutics, 42(4), 625633. https://doi.org/10.1016/j.clinthera.2020.02.011

Roberts, J. A., Abdul-Aziz, M. H., Lipman, J., Mouton, J. W., Vinks, A. A., Felton, T. W., Hope, W. W., Farkas, A., Neely, M. N., Schentag, J. J., Drusano, G., Frey, O. R., Theuretzbacher, U., & Kuti, J. L. (2014). Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. The Lancet Infectious Diseases, 14(6), 498509. https://doi.org/10.1016/S1473-3099(14)70036-2

Shrivastava, A., & Gupta, V. (2011). Methods for the determination of limit of detection and limit of quantitation of the analytical methods. Chronicles of Young Scientists, 2(1), 21. https://doi.org/10.4103/2229-5186.79345

The references used should be up to date (maximum of 10 years) and dominated of journal articles (at least 80%). It is highly recommended to use the reference manager to organize the references such as Zotero, Mendeley, Endnote, etc. The reference style used can be found in https://tinyurl.com/jpsc-csl. If you are a Mendeley user, you can install the journal's reference style by accessing https://csl.mendeley.com/styles/28740611/journal-of-pharmaceutical-sciences-and-community.

Timsit, J. F., Bassetti, M., Cremer, O., & Eggimann, P. (2017). Rationalizing antimicrobial therapy in the ICU: A narrative review. Intensive Care Medicine, 43(6), 885894. https://doi.org/10.1007/s00134-017-4686-2

Timsit, J. F., Bassetti, M., Cremer, O., Daikos, G., de Waele, J., Kallil, A., Kipnis, E., Kollef, M., Laupland, K., Paiva, J. A., Rodrguez-Bao, J., Rupp, ., Salluh, J., Taccone, F. S., Weiss, E., & Barbier, F. (2019). Rationalizing antimicrobial therapy in the ICU: a narrative review. In Intensive Care Medicine (Vol. 45, Issue 2, pp. 172189). Springer Verlag. https://doi.org/10.1007/s00134-019-05520-5

Titiesari, Y. D., & Febriani, F. (2021). Optimasi Penggunaan Antimikroba bagi Pasien Sepsis Berdasarkan Karakteristik Farmakokinetik dan Farmakodinamik Obat: Sebuah Tinjauan Literatur (Vol. 13).

U.S. Food and Drug Administration. (2022). Guidance for Industry: Population Pharmacokinetics.

Usman, M., Frey, O. R., & Hempel, G. (2017). Population pharmacokinetics of meropenem in elderly patients: dosing simulations based on renal function. European Journal of Clinical Pharmacology, 73(3), 333342. https://doi.org/10.1007/s00228-016-2172-4

Wei, A. A. J., Joshi, A., Chen, Y., & McIndoe, J. S. (2020). Strategies for avoiding saturation effects in ESI-MS. International Journal of Mass Spectrometry, 450, 116306. https://doi.org/10.1016/J.IJMS.2020.116306

Ye, X., Wang, F., Zeng, W., Ding, Y., & Lv, B. (2020). Comparison of empirical high-dose and low-dose of meropenem in critically ill patients with sepsis and septic shock: A randomized controlled study protocol. Medicine (United States), 99(51), E22829. https://doi.org/10.1097/MD.0000000000022829

Yonwises, W., Wacharachaisurapol, N., Anugulruengkitt, S., Maimongkol, P., & Treyaprasert, W. (2021). Population pharmacokinetics of meropenem in critically ill infant patients. International Journal of Infectious Diseases, 111, 5864. https://doi.org/10.1016/j.ijid.2021.08.031

Ycel, K., Abu?o?lu, S., & nl, A. (2018). Comparison of immunoassay and liquid chromatography-tandem mass spectrometry methods in the measurement of serum androstenedione levels. Clinical Laboratory, 64(12), 6975. https://doi.org/10.7754/Clin.Lab.2017.170612

DOI: https://doi.org/10.24071/jpsc.0011827