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Pharmacokinetic–pharmacodynamic study of itraconazole in patients with fungal infections in intensive care units

Abstract

Severely ill patients in intensive care units (ICU) are frequently at risk of developing fungal infections. Itraconazole (ITCZ), a triazole antifungal agent, is used for the treatment of aspergillosis, candidiasis, and cryptoccosis. The present retrospective pharmacokinetic–pharmacodynamic (PK–PD) analysis was designed to find any factors affecting clinical outcome of ITCZ treatment, and was performed to evaluate the appropriateness of the current dosage regimen in ICU patients. All of the patients admitted to Aichi Medical University Hospital ICU in 2008 who were treated with ITCZ injections for fungal infections were included in the study. After outcomes had been classified as cure or failure, a PK–PD analysis was performed. In addition, the probability of PD target attainment was assessed using a Monte Carlo simulation. Ten patients were enrolled in the study. Satisfactory outcomes were obtained in 4 of the 10 patients. No significant differences in the area under the 24-h curve (AUC0–24), peak concentrations and trough concentrations were observed between the two groups. However, it was observed that the higher the AUC0–24, the better the outcome. Moreover, our results showed that additional dosage is needed to attain a sufficiently high AUC0–24/MIC in about 20% of patients. Our retrospective study is the first to show that it is important to consider the host’s condition when ITCZ is administered, especially in ICU patients. The present findings are also useful for optimizing the individual dosage of ITCZ based on AUC0–4 for the treatment of patients infected with Candida spp.

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References

  1. Link H, Bohme A, Cornely OA, Höffken K, Kellner O, Kern WV, Mahlberg R, Maschmeyer G, Nowrousian MR, Ostermann H, Ruhnke M, Sezer O, Schiel X, Wilhelm M, Auner HW. Antimicrobial therapy of unexplained fever in neutropenic patients—guidelines of the Infectious Disease Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO), Study Group Interventional Therapy of Unexplained Fever, Arbeitsgemeinschaft Supportivmassnahmen in der Onkologie (ASO) of the Deutsche Krebsgesellschaft (DKG—German Cancer Society). Ann Hematol. 2003;82(Suppl 2):S105–17.

    Google Scholar 

  2. Klastersky J. Empirical antifungal therapy. Int J Antimicrob Agents. 2004;23:105–12.

    Google Scholar 

  3. Jun HX, Zhixiang S, Chun W, Reksodiputro AH, Ranuhardy D, Tamura K, Matsumoto T, Lee DG, Purushotaman SV, Lim V, Ahmed A, Hussain Y, Chua M, Ong A, Liu CY, Hsueh PR, Lin SF, Liu YC, Suwangool P, Jootar S, Picazo JJ. Clinical guidelines for the management of cancer patients with neutropenia and unexplained fever. Int J Antimicrob Agents. 2005;26(Suppl 2):S128–32.

    Google Scholar 

  4. Maertens J, Boogaerts M. The place for itraconazole in treatment. J Antimicrob Chemother. 2005;56(Suppl 1):i33–8.

    PubMed  Article  CAS  Google Scholar 

  5. Pappas PG, Rex JH, Sobel JD, Filler SG, Dismukes WE, Walsh TJ, Edwards JE. Guidelines for treatment of candidiasis. Clin Infect Dis. 2004;38:161–89.

    PubMed  Article  Google Scholar 

  6. Eggimann P, Garbino J, Pittet D. Management of Candida sepsis infections in critically ill patients. Lancet Infect Dis. 2003;3:772–85.

    PubMed  Article  CAS  Google Scholar 

  7. Vincent JL, Anaissie E, Bruining H, Demajo W, el-Ebiary M, Haber J, Hiramatsu Y, Nitenberg G, Nystrom PO, Pittet D, Rogers T, Sandven P, Sganga G, Schaller MD, Solomkin J. Epidemiology, diagnosis and treatment of systemic Candida infection in surgical patients under intensive care. Intensive Care Med. 1998;24:206–16.

    Google Scholar 

  8. Buchner T, Fegeler W, Bernhardt H, Brockmeyer N, Duswald KH, Herrmann M, Heuser D, Jehn U, Just-Nubling G, Karthaus M, Maschmeyer G, Müller FM, Müller J, Ritter J, Roos N, Ruhnke M, Schmalreck A, Schwarze R, Schwesinger G, Silling G. Treatment of severe Candida infections in high-risk patients in Germany: consensus formed by a panel of interdisciplinary investigators. Eur J Clin Microbiol Infect Dis. 2002;21:337–52.

    PubMed  Article  CAS  Google Scholar 

  9. Dimopoulos G, Karabinis A, Samonis G, Falagas ME. Candidemia in immunocompromised and immunocompetent critically ill patients: a prospective comparative study. Eur J Clin Microb Infect Dis. 2007;26:377–84.

    Article  CAS  Google Scholar 

  10. Wey SB, Mori M, Pfaller MA, Woolson RF, Wenzel RP. Risk factors for hospital-acquired candidemia. A matched case-control study. Arch Intern Med. 1989;149:2349–53.

    PubMed  Article  CAS  Google Scholar 

  11. Blumberg HM, Jarvis WR, Soucie JM, Edwars JE, Patterson JE, Pfaller MA, Rangel-Frausto MS, Rinaldi MG, Saiman L, Wiblin RT, Wenzel RP. Risk factors for Candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. The National Epidemiology of Mycosis Survey. Clin Infect Dis. 2001;33:177–86.

    Google Scholar 

  12. Pfaller MA, Diekema DJ. Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microb Rev. 2007;20:133–63.

    Article  CAS  Google Scholar 

  13. Patterson TF, Kirkpatrick WR, White M, Hiemenz JW, Wingard JR, Dupont B, Rinaldi MG, Stevens DA, Graybill JR. Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes. I3 Aspergillus Study Group. Medicine (Baltimore) 2000;79:250–60.

  14. Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis. 2001;32:358–66.

    PubMed  Article  CAS  Google Scholar 

  15. Wingard JR. Empirical antifungal therapy in treating febrile neutropenic patients. Clin Infect Dis. 2004;39(Suppl 1):S38–43.

    PubMed  Article  CAS  Google Scholar 

  16. Hostetler JS, Heykants J, Clemons KV, Woestenborghs R, Hanson LH, Stevens DA. Discrepancies in bioassay and chromatography determinations explained by metabolism of itraconazole to hydroxyitraconazole: studies of interpatient variations in concentrations. Antimicrob Agents Chemother. 1993;37:2224–7.

    PubMed  CAS  Google Scholar 

  17. Odds FC, Bossche HV. Antifungal activity of itraconazole compared with hydroxyl-itraconazole in vitro. J Antimicrob Chemother. 2000;45:371–3.

    PubMed  Article  CAS  Google Scholar 

  18. Glasmacher A, Hahn C, Leutner C, Molitor E, Wardelmann E, Losem C, Sauerbruch T, Marklein G, Schmidt-Wolf IG. Breakthrough invasive fungal infections in neutropenic patients after prophylaxis with itraconazole. Mycoses. 1999;42:443–51.

    PubMed  Article  CAS  Google Scholar 

  19. Glasmacher A, Hahn C, Molitor E, Marklein G, Sauerbruch T, Schmidt-Wolf IG. Itraconazole trough concentrations in antifungal prophylaxis with six different dosing regimens using hydroxypropyl-beta-cyclodextrin oral solution or coated-pellet capsules. Mycoses. 1999;42:591–600.

    PubMed  Article  CAS  Google Scholar 

  20. David A. In vivo pharmacodynamics of antifungal drugs in treatment of Candidiasis. Antimicrob Agents Chemother. 2003;47:1179–86.

    Article  Google Scholar 

  21. Burggess DS, Hastings RW. A comparison of dynamic characteristics of fluconazole, itraconazole, and amphotericin B against Cryptococcus neoformans using time–kill methodology. Diagn Microbil Infect Dis. 2000;38:87–93.

    Google Scholar 

  22. Manavathu EK, Cutright JL, Chandrasekar PH. Organism-dependent fungicidal activities of azoles. Antimicrob Agents Chemother. 1998;42:3018–21.

    PubMed  CAS  Google Scholar 

  23. Schafer-Korting M, Korting HC, Amann F, Peuser R, Lukacs A. Influence of albumin on itraconazole and ketoconazole antifungal activity: results of a dynamic in vitro study. Antimicrob Agents Chemother. 1991;35:2053–6.

    PubMed  CAS  Google Scholar 

  24. Schafer-Korting M, Korting HC, Ritter W, Obermuller W. Influence of serum protein binding on the in vitro activity of antifungal agents. Infection. 1995;23:292–7.

    PubMed  Article  CAS  Google Scholar 

  25. Zhanel GG, Saunders DG, Hoban DJ, Karlowsky JA. Influence of human serum on antifungal pharmacodynamics with Candida albicans. Antimicrob Agents Chemother. 2001;45:2018–22.

    PubMed  Article  CAS  Google Scholar 

  26. Andes D, Marchillo K, Stamstad T, Conklin R. In vivo pharmacokinetics and pharmacodynamics of a new triazole, voriconazole, in a murine candidiasis model. Antimicrob Agents Chemother. 2003;47:3165–9.

    PubMed  Article  CAS  Google Scholar 

  27. Andes D, van Ogtrop KM. Characterization and quantitation of the pharmacodynamics of fluconazole in a neutropenic murine disseminated candidiasis infection model. Antimicrob Agents Chemother. 1999;43:2116–20.

    Google Scholar 

  28. Boogaerts M, Winston DJ, Bow EJ, Garber G, Reboli AC, Schwarer AP, Novitzky N, Boehme A, Chwetzoff E, De Beule K. Intravenous and oral itraconazole versus intravenous amphotericin B dexycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy. A randomized, controlled trial. Ann Intern Med. 2001;135:412–22.

    PubMed  CAS  Google Scholar 

  29. Prentice AG, Glasmacher A. Making sense of itraconazole pharmacokinetics. J Antimicrob Chemother. 2005;56(Suppl 1):i17–22.

    PubMed  Article  CAS  Google Scholar 

  30. Heykants J, Van Peer A, Van de Velde V, Van Rooy P, Meuldermans W, Lavrijsen K, Woestenborghs R, Van Cutsem J, Cauwenbergh G. The clinical pharmacokinetics of itraconazole: an overview. Mycoses. 1989;32(Suppl 1):67–87.

    PubMed  Google Scholar 

  31. Okuda T, Watanabe N, Okuda A, Takao M, Takayanagi K. Monitoring the plasma level of itraconazole administration for prevention of fungal infection: the relationship between the plasma itraconazole level and several clinical parameters. Jpn J TDM. 2008;25:8–12.

    Google Scholar 

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Acknowledgments

We thank the clinicians and pharmacists that have assisted with the provision of data for this project.

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Correspondence to Mao Hagihara.

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Hagihara, M., Kasai, H., Umemura, T. et al. Pharmacokinetic–pharmacodynamic study of itraconazole in patients with fungal infections in intensive care units. J Infect Chemother 17, 224–230 (2011). https://doi.org/10.1007/s10156-010-0102-4

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  • DOI: https://doi.org/10.1007/s10156-010-0102-4

Keywords

  • Itraconazole
  • Candida
  • Pharmacokinetics–pharmacodynamics (PK–PD)