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Licensed Unlicensed Requires Authentication Published by De Gruyter July 12, 2021

Simple and accurate quantitative analysis of cefiderocol and ceftobiprole in human plasma using liquid chromatography-isotope dilution tandem mass spectrometry: interest for their therapeutic drug monitoring and pharmacokinetic studies

  • Benoit Llopis , Alexandre Bleibtreu , Dimitri Schlemmer , Pascal Robidou , Olivier Paccoud , Nadine Tissot , Gaëlle Noé , Helga Junot , Charles-Édouard Luyt , Christian Funck-Brentano and Noël Zahr EMAIL logo

Abstract

Objectives

Cefiderocol and ceftobiprole are new generation cephalosporin antibiotics that exhibit high inter-individual plasma concentration variability that potentially impact their efficacy or toxicity. The aim of this study was to develop and validate a selective, simple, and fast UPLC-MS/MS method for simultaneous quantification of cefiderocol and ceftobiprole in human plasma to enable their therapeutic drug monitoring (TDM) and support PK and PK/PD studies, in particular in critically ill patients.

Methods

After a simple and fast single-step protein precipitation, cefiderocol and ceftobiprole were separated on a Waters Acquity UPLC BEH C18 column by linear gradient elution; with subsequent detection by Shimadzu MS 8060 triple quadrupole tandem mass spectrometer in a positive ionization mode.

Results

Analysis time was 5 min per run. The analytical performance of the method in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect (ME), extraction recovery (ER), limit of quantification, dilution integrity, and stability of analytes under different conditions met all criteria for a bioanalytical method for the quantification of drugs. The calibration curves were linear over the range of 1–200 mg/L for cefiderocol and 0.5–100 mg/L for ceftobiprole with a linear regression coefficient above 0.995 for both.

Conclusions

A simple, fast, and selective liquid chroma-tography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of cefiderocol and ceftobiprole. This new method was successfully applied to the measurement of plasma concentration of cefiderocol and ceftobiprole in critically ill patients and showed good performance for their therapeutic monitoring and optimizing antibiotic therapy.


Corresponding author: Dr. Noël Zahr, AP-HP. Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Pharmacology, CIC-1901, Pharmacokinetics and Therapeutic Drug Monitoring Unit, UMR-S 1166, Paris, France; and AP-HP. Sorbonne Université, Laboratoire de suivi thérapeutique pharmacologique spécialisé, Paris, France, Phone: +33 1 42 16 20 15, Fax: +33 1 42 16 20 46, E-mail:

  1. Research funding: None declared.

  2. Author contributions: B.L: Conceptualization, investigation, validation, data analysis, visualization, writing-original draft, writing-review and editing. A.B: investigation, writing-review and editing. D.S: investigation. P.R: investigation. O.P: investigation, writing-review and editing. N.T: investigation, writing-review and editing. G.N: investigation, writing-review and editing. H.J: investigation, writing-review and editing. CE.L: investigation, writing-review and editing. C.FB: investigation, writing-review and editing. N.Z: supervision, conceptualization, investigation, writing-review and editing. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: A.B has received fees from Shionogi, the manufacturer of cefiderocol. CE.L has received grant and travel fees from Correvio, the manufacturer of ceftobiprol. Other authors state no conflict of interest.

  4. Informed consent: Not applicable. French regulations on non-interventional observational studies do not require patient's consent when analyzing data obtained from routine care.

  5. Ethical approval: Approval for data collection was obtained from the Commission Nationale de l’Informatique et des Libertés (n°1491960v0).

References

1. Morosini, MI, Diez-Aguilar, M, Canton, R. Mechanisms of action and antimicrobial activity of ceftobiprole. Rev Española Quimioter 2019;32(3 Suppl):3–10.Search in Google Scholar

2. Torres, A, Ferrer, M, Badia, JR. Treatment guidelines and outcomes of hospital-acquired and ventilator-associated pneumonia. Clin Infect Dis 2010;51(1 Suppl):S48–53. https://doi.org/10.1086/653049.Search in Google Scholar

3. Welte, T, Torres, A, Nathwani, D. Clinical and economic burden of community-acquired pneumonia among adults in Europe. Thorax 2012;67:71–9. https://doi.org/10.1136/thx.2009.129502.Search in Google Scholar

4. Awad, SS, Rodriguez, AH, Chuang, YC, Marjanek, Z, Pareigis, AJ, Reis, G, et al.. A phase 3 randomized double-blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital-acquired pneumonia. Clin Infect Dis 2014;59:51–61. https://doi.org/10.1093/cid/ciu219.Search in Google Scholar

5. Nicholson, SC, Welte, T, File, TMJr, Strauss, RS, Michiels, B, Kaul, P, et al.. A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation. Int J Antimicrob Agents 2012;39:240–6. https://doi.org/10.1016/j.ijantimicag.2011.11.005.Search in Google Scholar

6. Torres, A, Mouton, JW, Pea, F. Pharmacokinetics and dosing of ceftobiprole medocaril for the treatment of hospital- and community-acquired pneumonia in different patient populations. Clin Pharmacokinet 2016;55:1507–20. https://doi.org/10.1007/s40262-016-0418-z.Search in Google Scholar

7. Muller, AE, Punt, N, Mouton, JW. Exposure to ceftobiprole is associated with microbiological eradication and clinical cure in patients with nosocomial pneumonia. Antimicrob Agents Chemother 2014;58:2512–9. https://doi.org/10.1128/aac.02611-13.Search in Google Scholar

8. Lima, B, Bodeau, S, Quinton, MC, Leven, C, Lemaire-Hurtel, AS, Bennis, Y. Validation and application of an HPLC-DAD method for routine therapeutic drug monitoring of ceftobiprole. Antimicrob Agents Chemother 2019;63. https://doi.org/10.1128/AAC.00515-19.Search in Google Scholar

9. Andrei, S, Droc, G, Stefan, G. FDA approved antibacterial drugs: 2018-2019. Discoveries 2019;7:e102. https://doi.org/10.15190/d.2019.15.Search in Google Scholar

10. CDC. Antibiotic-resistant germs: new threats [Internet]. Centers for Disease Control and Prevention; 2021. Available from: https://www.cdc.gov/drugresistance/biggest-threats.html.Search in Google Scholar

11. Meletis, G, Exindari, M, Vavatsi, N, Sofianou, D, Diza, E. Mechanisms responsible for the emergence of carbapenem resistance in Pseudomonas aeruginosa. Hippokratia 2012;16:303–7.Search in Google Scholar

12. Tillotson, GS. Trojan horse antibiotics-a novel way to circumvent Gram-negative bacterial resistance? Infect Dis (Auckl) 2016;9:45–52. https://doi.org/10.4137/IDRT.S31567.Search in Google Scholar

13. Nordmann, P, Poirel, L. Epidemiology and diagnostics of carbapenem resistance in Gram-negative bacteria. Clin Infect Dis 2019;69(7 Suppl):S521–S8. https://doi.org/10.1093/cid/ciz824.Search in Google Scholar

14. Morrill, HJ, Pogue, JM, Kaye, KS, LaPlante, KL. Treatment options for carbapenem-resistant Enterobacteriaceae infections. Open Forum Infect Dis 2015;2:ofv050. https://doi.org/10.1093/ofid/ofv050.Search in Google Scholar

15. Doi, Y. Treatment options for carbapenem-resistant Gram-negative bacterial infections. Clin Infect Dis 2019;69(7 Suppl):S565–S75. https://doi.org/10.1093/cid/ciz830.Search in Google Scholar

16. Hackel, MA, Tsuji, M, Yamano, Y, Echols, R, Karlowsky, JA, Sahm, DF. In vitro activity of the siderophore cephalosporin, cefiderocol, against a recent collection of clinically relevant Gram-negative bacilli from North America and Europe, including carbapenem-nonsusceptible isolates (SIDERO-WT-2014 study). Antimicrob Agents Chemother 2017;61:e00093-17. https://doi.org/10.1128/aac.00093-17.Search in Google Scholar

17. Portsmouth, S, van Veenhuyzen, D, Echols, R, Machida, M, Ferreira, JCA, Ariyasu, M, et al.. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis 2018;18:1319–28. https://doi.org/10.1016/s1473-3099(18)30554-1.Search in Google Scholar

18. Saisho, Y, Katsube, T, White, S, Fukase, H, Shimada, J. Pharmacokinetics, safety, and tolerability of cefiderocol, a novel siderophore cephalosporin for Gram-negative bacteria, in healthy subjects. Antimicrob Agents Chemother 2018;62:e02163-17. https://doi.org/10.1128/AAC.02163-17.Search in Google Scholar

19. Kawaguchi, N, Katsube, T, Echols, R, Wajima, T. Population pharmacokinetic analysis of cefiderocol, a parenteral siderophore cephalosporin, in healthy subjects, subjects with various degrees of renal function, and patients with complicated urinary tract infection or acute uncomplicated pyelonephritis. Antimicrob Agents Chemother 2018;62:e01391-17. https://doi.org/10.1128/AAC.01391-17.Search in Google Scholar

20. Katsube, T, Echols, R, Arjona Ferreira, JC, Krenz, HK, Berg, JK, Galloway, C. Cefiderocol, a siderophore cephalosporin for Gram-negative bacterial infections: pharmacokinetics and safety in subjects with renal impairment. J Clin Pharmacol 2017;57:584–91. https://doi.org/10.1002/jcph.841.Search in Google Scholar

21. Kawaguchi, N, Katsube, T, Echols, R, Wajima, T. Population pharmacokinetic and pharmacokinetic/pharmacodynamic analyses of cefiderocol, a parenteral siderophore cephalosporin, in patients with pneumonia, bloodstream infection/sepsis, or complicated urinary tract infection. Antimicrob Agents Chemother 2021;65:e01437-20. https://doi.org/10.1128/AAC.01437-20.Search in Google Scholar

22. Neuner, EA, Gallagher, JC. Pharmacodynamic and pharmacokinetic considerations in the treatment of critically Ill patients infected with carbapenem-resistant Enterobacteriaceae. Virulence 2017;8:440–52. https://doi.org/10.1080/21505594.2016.1221021.Search in Google Scholar

23. Parker, SL, Abdul-Aziz, MH, Roberts, JA. The role of antibiotic pharmacokinetic studies performed post-licensing. Int J Antimicrob Agents 2020;56:106165. https://doi.org/10.1016/j.ijantimicag.2020.106165.Search in Google Scholar

24. Abdul-Aziz, MH, Lipman, J, Akova, M, Bassetti, M, De Waele, JJ, Dimopoulos, G, et al.. Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort. J Antimicrob Chemother 2016;71:196–207. https://doi.org/10.1093/jac/dkv288.Search in Google Scholar

25. Scharf, C, Liebchen, U, Paal, M, Taubert, M, Vogeser, M, Irlbeck, M, et al.. 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. https://doi.org/10.1186/s40560-020-00504-w.Search in Google Scholar

26. Gatti, M, Pea, F. Pharmacokinetic/pharmacodynamic target attainment in critically ill renal patients on antimicrobial usage: focus on novel beta-lactams and beta lactams/beta-lactamase inhibitors. Expet Rev Clin Pharmacol 2021;14:583–99. https://doi.org/10.1080/17512433.2021.1901574.Search in Google Scholar

27. European Medicines Agency. Bioanalytical method validation; 2011. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-bioanalytical-method-validation_en.pdf.Search in Google Scholar

28. Matuszewski, BK, Constanzer, ML, Chavez-Eng, CM. Strategies for the assessment of matrix effect in quantitative bioanalytical methods based on HPLC-MS/MS. Anal Chem 2003;75:3019–30. https://doi.org/10.1021/ac020361s.Search in Google Scholar

29. Mernissi, T, Bodeau, S, Andre, C, Zahr, N, Mary, A, Dupont, H, et al.. An HPLC assay for the therapeutic drug monitoring of cefiderocol in critically ill patients. J Antimicrob Chemother 2021;76:1643–6. https://doi.org/10.1093/jac/dkab051.Search in Google Scholar

30. Zimmer, J, Rohr, AC, Kluge, S, Faller, J, Frey, OR, Wichmann, D, et al.. Validation and application of an HPLC-UV method for routine therapeutic drug monitoring of cefiderocol. Antibiotics 2021;10:242. https://doi.org/10.3390/antibiotics10030242.Search in Google Scholar

31. Pitt, JJ. Principles and applications of liquid chromatography-mass spectrometry in clinical biochemistry. Clin Biochem Rev 2009;30:19–34.Search in Google Scholar

32. Miyazaki, S, Katsube, T, Shen, H, Tomek, C, Narukawa, Y. Metabolism, excretion, and pharmacokinetics of [(14) C]-Cefiderocol (S-649266), a siderophore cephalosporin, in healthy subjects following intravenous administration. J Clin Pharmacol 2019;59:958–67. https://doi.org/10.1002/jcph.1386.Search in Google Scholar

33. Schmitt-Hoffmann, A, Nyman, L, Roos, B, Schleimer, M, Sauer, J, Nashed, N, et al.. Multiple-dose pharmacokinetics and safety of a novel broad-spectrum cephalosporin (BAL5788) in healthy volunteers. Antimicrob Agents Chemother 2004;48:2576–80. https://doi.org/10.1128/aac.48.7.2576-2580.2004.Search in Google Scholar


Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2021-0423).


Received: 2021-04-08
Accepted: 2021-06-21
Published Online: 2021-07-12
Published in Print: 2021-10-26

© 2021 Walter de Gruyter GmbH, Berlin/Boston

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