Pharmacokinetic variability and target attainment of fluconazole in critically ill patients

[en] Background: Fluconazole is one of the oldest antifungal drugs. Previous studies have raised concerns considering variability in exposure and inadequate target attainment in critically ill pa-tients. The current study aims to define variability and target attainment for fluconazole exposure in a large group of critically ill patients. Methods: In this pharmacokinetic study, daily plasma trough samples and, if possible, 24 h urine samples were collected to determine fluconazole concentration. A minimum target trough concentration of 10–15 mg/L was selected, corresponding to a free area under the concentration–time curve above the minimum inhibitory concentration (fAUC/MIC) of at least 100 for an MIC of 4 mg/L. Covariates that significantly influenced fluconazole exposure were identified. Results: In total, 288 plasma samples from 43 patients, with a median age of 66 years, were included. The median fluconazole trough concentration was 22.9 mg/L. A notable component of the measured concentrations was below the target trough concentrations (13% <10 mg/L and 27% <15 mg/L). The intra-and intersubject variability were 28.3% and 50.5%, respectively. The main covariates determining fluconazole exposure were the administered dose (mg/kg), augmented renal clearance, and renal replacement therapy. Conclusions: Fluconazole trough concentrations are variable in critically ill patients and a considerable number of these concentrations was below the pre-defined target trough concentrations. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Disciplines :

Laboratory medicine & medical technology

Author, co-author :

Van Daele, R.; Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, 3000, Belgium, Pharmacy Department, University Hospitals Leuven, Leuven, 3000, Belgium

Wauters, J.; Laboratory for Clinical Infectious and Inflammatory Disorders, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, 3000, Belgium, Medical Intensive Care Unit, University Hospitals Leuven, Leuven, 3000, Belgium

Lagrou, K.; Clinical Department of Laboratory Medicine and National Reference Centre for Mycosis, Excellence Centre for Medical Mycology (ECMM), University Hospitals Leuven, Leuven, 3000, Belgium, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, 3000, Belgium

Denooz, Raphael ; Centre Hospitalier Universitaire de Liège - CHU > > Service de toxicologie clinique, médicolégale, environnementale et en entreprise

Hayette, Marie-Pierre ; Centre Hospitalier Universitaire de Liège - CHU > > Service de microbiologie clinique

Gijsen, M.; Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, 3000, Belgium, Pharmacy Department, University Hospitals Leuven, Leuven, 3000, Belgium

Brüggemann, R.J.; Department of Pharmacy and Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, 6525 GA, Netherlands, Center of Expertise in Mycology Radboudumc/CWZ, Radboud University Medical Center, Nijmegen, 6525 GA, Netherlands

Debaveye, Y.; Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, 3000, Belgium, Intensive Care Unit, University Hospitals Leuven, Leuven, 3000, Belgium

Spriet, I.; Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, 3000, Belgium, Pharmacy Department, University Hospitals Leuven, Leuven, 3000, Belgium

Language :

English

Title :

Pharmacokinetic variability and target attainment of fluconazole in critically ill patients

Publication date :

2021

Journal title :

Microorganisms

eISSN :

2076-2607

Publisher :

MDPI

Volume :

Issue :

Peer reviewed :

Peer Reviewed verified by ORBi

Funding text :

Conflicts of Interest: J.W. reports grants from M.S.D. during the conduct of the study. J.W. received speaker fees, travel grants, and investigator-initiated grants from M.S.D., Gilead, and Pfizer, outside of the submitted work. K.L. received consultancy fees from SMB Laboratoires Brussels and Gilead, travel support from Pfizer, speaker fees from FUJIFILM WAKO and Pfizer, and a grant from Thermo Fisher Scientific. M.-P.H. received travel support and speaker fees from Pfizer, travel support from Gilead, and M.S.D. R.B. reports and is consultant to F2G, Mundipharma, and Amplyx and has received unrestricted grants in the past five years from Gilead, Pfizer, M.S.D., and Astellas. He has provided lectures for Gilead and Pfizer. All contracts were with Radboudumc and all invoices were paid to Radboudumc. I.S. is supported by the Clinical Research Fund of UZ Leuven and served as a consultant to, and has received unrestricted travel and research grants from, Gilead Sciences, Merck Sharpe and Dohme Corp., Pfizer Inc., and Cidara. All contracts were through and invoiced by UZ and KU Leuven. R.V.D., R.D., M.G., and Y.D. have nothing to disclose.

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since 21 October 2022

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Bibliography

Pfizer. Summary of Product Characteristics (SmPC) Diflucan.Available online: https://www.ema.europa.eu/en/documents/referral/diflucan-article-30-referral-annex-iii_en.pdf (accessed on 02/02/2012)
Gijsen, M.; Wilmer, A.; Meyfroidt, G.; Wauters, J.; Spriet, I. Can augmented renal clearance be detected using estimators of glomerular filtration rate? Crit. Care 2020, 24, 359, doi:10.1186/s13054-020-03057-4.
Smith, B.S.; Yogaratnam, D.; Levasseur-Franklin, K.E.; Forni, A.; Fong, J. Introduction to drug pharmacokinetics in the critically ill patient. Chest 2012, 141, 1327–1336, doi:10.1378/chest.11-1396.
Alobaid, A.S.; Wallis, S.C.; Jarrett, P.; Starr, T.; Stuart, J.; Lassig-Smith, M.; Mejia, J.L.; Roberts, M.S.; Sinnollareddy, M.G.; Roger, C.; et al. Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients. Antimicrob. Agents Chemother. 2016, 60, 6550–6557, doi:10.1128/aac.01088-16.
Gharibian, K.N.; Mueller, B.A. Fluconazole dosing predictions in critically-ill patients receiving prolonged intermittent renal replacement therapy: A Monte Carlo simulation approach. Clin. Nephrol. 2016, 86, 43–50, doi:10.5414/cn108824.
Patel, K.; Roberts, J.A.; Lipman, J.; Tett, S.E.; Deldot, M.E.; Kirkpatrick, C.M. Population pharmacokinetics of fluconazole in critically ill patients receiving continuous venovenous hemodiafiltration: Using Monte Carlo simulations to predict doses for specified pharmacodynamic targets. Antimicrob. Agents Chemother. 2011, 55, 5868–5873, doi:10.1128/aac.00424-11.
Lopez, N.D.; Phillips, K.M. Fluconazole pharmacokinetics in a morbidly obese, critically ill patient receiving continuous venovenous hemofiltration. Pharmacotherapy 2014, 34, e162–e168, doi:10.1002/phar.1470.
Sinnollareddy, M.G.; Roberts, J.A.; Lipman, J.; Akova, M.; Bassetti, M.; De Waele, J.J.; Kaukonen, K.M.; Koulenti, D.; Martin, C.; Montravers, P.; et al. Pharmacokinetic variability and exposures of fluconazole, anidulafungin, and caspofungin in intensive care unit patients: Data from multinational Defining Antibiotic Levels in Intensive care unit (DALI) patients Study. Crit. Care 2015, 19, 33, doi:10.1186/s13054-015-0758-3.
Muilwijk, E.W.; de Lange, D.W.; Schouten, J.A.; Wasmann, R.E.; Ter Heine, R.; Burger, D.M.; Colbers, A.; Haas, P.J.; Verweij, P.E.; Pickkers, P.; et al. Suboptimal Dosing of Fluconazole in Critically Ill Patients: Time To Rethink Dosing. Antimicrob. Agents Chemother. 2020, 64, e00984–e00920, doi:10.1128/aac.00984-20.
Boonstra, J.M.; Märtson, A.G.; Sandaradura, I.; Kosterink, J.G.W.; van der Werf, T.S.; Marriott, D.J.E.; Zijlstra, J.G.; Touw, D.J.; Alffenaar, J.W.C. Optimization of Fluconazole Dosing for the Prevention and Treatment of Invasive Candidiasis Based on the Pharmacokinetics of Fluconazole in Critically Ill Patients. Antimicrob. Agents Chemother. 2021, 65, e01554-01520, doi:10.1128/aac.01554-20.
Pappas, P.G.; Kauffman, C.A.; Andes, D.R.; Clancy, C.J.; Marr, K.A.; Ostrosky-Zeichner, L.; Reboli, A.C.; Schuster, M.G.; Vazquez, J.A.; Walsh, T.J.; et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 2016, 62, e1–e50, doi:10.1093/cid/civ933.
Chen, J.; Tian, S.; Han, X.; Chu, Y.; Wang, Q.; Zhou, B.; Shang, H. Is the superbug fungus really so scary? A systematic review and meta-analysis of global epidemiology and mortality of Candida auris. BMC Infect Dis 2020, 20, 827, doi:10.1186/s12879-020-05543-0.
Cornely, O.A.; Bassetti, M.; Calandra, T.; Garbino, J.; Kullberg, B.J.; Lortholary, O.; Meersseman, W.; Akova, M.; Arendrup, M.C.; Arikan-Akdagli, S.; et al. ESCMID* guideline for the diagnosis and management of Candida diseases 2012: Non-neutropenic adult patients. Clin. Microbiol. Infect. Off. Publ. Eur. Soc. Clin. Microbiol. Infect. Dis. 2012, 18 Suppl 7, 19-37, doi:10.1111/1469-0691.12039.
Martin-Loeches, I.; Antonelli, M.; Cuenca-Estrella, M.; Dimopoulos, G.; Einav, S.; De Waele, J.J.; Garnacho-Montero, J.; Kanj, S.S.; Machado, F.R.; Montravers, P.; et al. ESICM/ESCMID task force on practical management of invasive candidiasis in critically ill patients. Intensive Care Med. 2019, 45, 789–805, doi:10.1007/s00134-019-05599-w.
Kett, D.H.; Shorr, A.F.; Reboli, A.C.; Reisman, A.L.; Biswas, P.; Schlamm, H.T. Anidulafungin compared with fluconazole in severely ill patients with candidemia and other forms of invasive candidiasis: Support for the 2009 IDSA treatment guidelines for candidiasis. Crit. Care (Lond. Engl.) 2011, 15, R253, doi:10.1186/cc10514.
López-Cortés, L.E.; Almirante, B.; Cuenca-Estrella, M.; Garnacho-Montero, J.; Padilla, B.; Puig-Asensio, M.; Ruiz-Camps, I.; Rodríguez-Baño, J. Empirical and targeted therapy of candidemia with fluconazole versus echinocandins: A propensity score-derived analysis of a population-based, multicentre prospective cohort. Clin. Microbiol. Infect. Off. Publ. Eur. Soc. Clin. Microbiol. Infect. Dis. 2016, 22, 733.e731–e738, doi:10.1016/j.cmi.2016.05.008.
Debruyne, D.; Ryckelynck, J.P. Clinical pharmacokinetics of fluconazole. Clin. Pharmacokinet. 1993, 24, 10–27, doi:10.2165/00003088-199324010-00002.
Wade, K.C.; Benjamin, D.K., Jr.; Kaufman, D.A.; Ward, R.M.; Smith, P.B.; Jayaraman, B.; Adamson, P.C.; Gastonguay, M.R.; Barrett, J.S. Fluconazole dosing for the prevention or treatment of invasive candidiasis in young infants. Pediatr. Infect Dis. J. 2009, 28, 717–723, doi:10.1097/INF.0b013e31819f1f50.
Pea, F.; Righi, E.; Cojutti, P.; Carnelutti, A.; Baccarani, U.; Soardo, G.; Bassetti, M. Intra-abdominal penetration and pharmacodynamic exposure to fluconazole in three liver transplant patients with deep-seated candidiasis. J. Antimicrob. Chemother. 2014, 69, 2585–2586, doi:10.1093/jac/dku169.
European Committee on Antimicrobial Susceptibility Testing (EUCAST). Rationale for EUCAST clinical breakpoints. Fluconazole. Version 3.0. 2020. Available online: https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Rationale_documents/Fluconazole_RD_v3.0_final_18_02.pd f (accessed on 21 September 2021).
van der Elst, K.C.; Pereboom, M.; van den Heuvel, E.R.; Kosterink, J.G.; Schölvinck, E.H.; Alffenaar, J.W. Insufficient fluconazole exposure in pediatric cancer patients and the need for therapeutic drug monitoring in critically ill children. Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 2014, 59, 1527–1533, doi:10.1093/cid/ciu657.
Lewis, R.; Brüggemann, R.; Padoin, C.; Maertens, J.; Marchetti, O.; Groll, A.; Johnson, E.; Arendrup, M. Triazole Antifungal Therapeutic Drug Monitoring. In Proceedings of the ECIL 6 Meeting, Sophia Antipolis, France, 11–12 september 2015.
Mistretta, V.; Dubois, N.; Denooz, R.; Charlier, C. Simultaneous determination of seven azole antifungal drugs in serum by ultra-high pressure liquid chromatography and diode array detection. Acta Clin. Belg. 2014, 69, 53–61, doi:10.1179/0001551213z.00000000018.
ClinCalc.com. APACHE II Calculator. Available online: https://clincalc.com/IcuMortality/APACHEII.aspx, accessed 19 July 2019
Ceesay, M.M.; Couchman, L.; Smith, M.; Wade, J.; Flanagan, R.J.; Pagliuca, A. Triazole antifungals used for prophylaxis and treatment of invasive fungal disease in adult haematology patients: Trough serum concentrations in relation to outcome. Med. Mycol. 2016, 54, 691–698, doi:10.1093/mmy/myw031.
El-Yazigi, A.; Ellis, M.; Ernst, P.; Hussein, R.; Baillie, F.J. Effect of repeated dosing on the pharmacokinetics of oral fluconazole in bone marrow transplant patients. J. Clin. Pharmacol. 1997, 37, 1031–1037, doi:10.1002/j.1552-4604.1997.tb04284.x.
Bergner, R.; Hoffmann, M.; Riedel, K.D.; Mikus, G.; Henrich, D.M.; Haefeli, W.E.; Uppenkamp, M.; Walter-Sack, I. Fluconazole dosing in continuous veno-venous haemofiltration (CVVHF): Need for a high daily dose of 800 mg. Nephrol Dial. Transpl. 2006, 21, 1019–1023, doi:10.1093/ndt/gfi284.
Matana, A.; Zaninović Jurjević, T.; Matana Kaštelan, Z. Can the difference in serum concentration of urea and cystatin C be used in diagnosis and prognosis of heart failure? Med. Hypotheses 2014, 83, 401–403, doi:10.1016/j.mehy.2014.07.005.
Gijsen, M.; Huang, C.Y.; Flechet, M.; Van Daele, R.; Declercq, P.; Debaveye, Y.; Meersseman, P.; Meyfroidt, G.; Wauters, J.; Spriet, I. Development and External Validation of an Online Clinical Prediction Model for Augmented Renal Clearance in Adult Mixed Critically Ill Patients: The Augmented Renal Clearance Predictor. Crit. Care Med. 2020, 48, e1260–e1268, doi:10.1097/ccm.0000000000004667.
Leroy, G.; Lambiotte, F.; Thévenin, D.; Lemaire, C.; Parmentier, E.; Devos, P.; Leroy, O. Evaluation of “Candida score” in critically ill patients: A prospective, multicenter, observational, cohort study. Ann. Intensive Care 2011, 1, 50, doi:10.1186/2110-5820-1-50.
Brammer, K.W.; Coakley, A.J.; Jezequel, S.G.; Tarbit, M.H. The disposition and metabolism of [14C]fluconazole in humans. Drug Metab. Dispos. Biol. Fate Chem. 1991, 19, 764–767.
Giannini, E.G.; Testa, R.; Savarino, V. Liver enzyme alteration: A guide for clinicians. Cmaj 2005, 172, 367–379, doi:10.1503/cmaj.1040752.
Matsumoto, K.; Ueno, K.; Yoshimura, H.; Morii, M.; Takada, M.; Sawai, T.; Mitsutake, K.; Shibakawa, M. Fluconazole-induced convulsions at serum trough concentrations of approximately 80 microg/mL. Ther. Drug Monit. 2000, 22, 635–636, doi:10.1097/00007691-200010000-00022.
Tortorano, A.M.; Kibbler, C.; Peman, J.; Bernhardt, H.; Klingspor, L.; Grillot, R. Candidaemia in Europe: Epidemiology and resistance. Int. J. Antimicrob. Agents 2006, 27, 359–366, doi:10.1016/j.ijantimicag.2006.01.002.
Trouvé, C.; Blot, S.; Hayette, M.P.; Jonckheere, S.; Patteet, S.; Rodriguez-Villalobos, H.; Symoens, F.; Van Wijngaerden, E.; Lagrou, K. Epidemiology and reporting of candidaemia in Belgium: A multi-centre study. Eur. J. Clin. Microbiol. Infect Dis. 2017, 36, 649–655, doi:10.1007/s10096-016-2841-3.
Sandaradura, I.; Wojciechowski, J.; Marriott, D.J.E.; Day, R.O.; Stocker, S.; Reuter, S.E. Model-Optimized Fluconazole Dose Selection for Critically Ill Patients Improves Early Pharmacodynamic Target Attainment without the Need for Therapeutic Drug Monitoring. Antimicrob. Agents Chemother. 2021, 65, e02019-20, doi:10.1128/aac.02019-20.