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01-02-2007 | Original Article

Itraconazole prophylaxis in pediatric cancer patients receiving conventional chemotherapy or autologous stem cell transplants

Authors: Arne Simon, Mette Besuden, Sandra Vezmar, Carola Hasan, Dagmar Lampe, Sigrid Kreutzberg, Axel Glasmacher, Udo Bode, Gudrun Fleischhack

Published in: Supportive Care in Cancer | Issue 2/2007

Abstract

Goal of work

During the renovation works at our institution, the incidence density for invasive aspergillosis (IA) increased from <0.5 to 0.99/1,000 inpatient days in 2001. As a direct response to this increased environmental risk, itraconazole (ITC) was administered for primary prophylaxis in pediatric cancer patients for whom a particular high risk of IA was anticipated due to prolonged severe neutropenia (>10 days), autologous stem cell transplantation, acute myeloblastic leukemia or relapsed acute lymphoblastic leukemia, or high-dose steroids >3 weeks.

Materials and methods

In this open-label, prospective observational study, ITC was given in ITC solution or capsule. Trough concentrations were measured in plasma with high-performance liquid chromatography after at least 7 days of treatment. Doses were adjusted to target plasma trough ITC concentrations ≥0.5 mg/l.

Results

From 2001 to 2005, 39 pediatric cancer patients received 44 prophylactic ITC cycles; 102 trough plasma concentrations were measured after oral administration. Plasma target concentrations >0.5 mg/l were achieved with both formulations. A median dose of 8 mg kg⁻¹ day⁻¹ (3.5–16.0 mg kg⁻¹ day⁻¹) was necessary in pediatric oncology patients. The bioavailability of the liquid formulation was significantly lower when the solution was given by a feeding tube. Adverse effects (gastrointestinal, elevated transaminases, and one hemolysis) which led to the cessation of the ITC prophylaxis were reported in 11% of all courses. No breakthrough infection was seen in this pediatric population.

Conclusion

Oral ITC offers a feasible and inexpensive option for antifungal prophylaxis in selected pediatric cancer patients. Drug monitoring and meticulous consideration of possible interactions and adverse effects are mandatory.

Wright JA, Bradfield SM, Park JR, Hawkins DS (2003) Prolonged survival after invasive aspergillosis: a single-institution review of 11 cases. J Pediatr Hematol Oncol 25(4):286–291PubMedCrossRef

Creutzig U, Zimmermann M, Reinhardt D, Dworzak M, Stary J, Lehrnbecher T (2004) Early deaths and treatment-related mortality in children undergoing therapy for acute myeloid leukemia: analysis of the multicenter clinical trials AML-BFM 93 and AML-BFM 98. J Clin Oncol 22(21):4384–4393PubMedCrossRef

Lin SJ, Schranz J, Teutsch SM (2001) Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis 32(3):358–366PubMedCrossRef

Humphreys H (2004) Positive-pressure isolation and the prevention of invasive aspergillosis. What is the evidence? J Hosp Infect 56(2):93–100, quiz 163PubMedCrossRef

Manuel RJ, Kibbler CC (1998) The epidemiology and prevention of invasive aspergillosis. J Hosp Infect 39(2):95–109PubMedCrossRef

Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, Denning DW, Donnelly JP, Edwards JE et al (2002) Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 34(1):7–14PubMedCrossRef

Simon A, Fleischhack G, Hasan C, Bode U, Engelhart S, Kramer MH (2000) Surveillance for nosocomial and central line-related infections among pediatric hematology–oncology patients. Infect Control Hosp Epidemiol 21(9):592–596PubMedCrossRef

Cooper EE, O’Reilly MA, Guest DI, Dharmage SC (2003) Influence of building construction work on Aspergillus infection in a hospital setting. Infect Control Hosp Epidemiol 24(7):472–476PubMedCrossRef

Denning DW, Tucker RM, Hanson LH, Stevens DA (1989) Treatment of invasive aspergillosis with itraconazole. Am J Med 86(6 Pt 2):791–800PubMedCrossRef

10.

Caillot D, Bassaris H, McGeer A, Arthur C, Prentice HG, Seifert W, De Beule K (2001) Intravenous itraconazole followed by oral itraconazole in the treatment of invasive pulmonary aspergillosis in patients with hematologic malignancies, chronic granulomatous disease, or AIDS. Clin Infect Dis 33(8):e83–e90PubMedCrossRef

11.

de Repentigny L, Ratelle J, Leclerc JM, Cornu G, Sokal EM, Jacqmin P, De Beule K (1998) Repeated-dose pharmacokinetics of an oral solution of itraconazole in infants and children. Antimicrob Agents Chemother 42(2):404–408PubMed

12.

Groll AH, Wood L, Roden M, Mickiene D, Chiou CC, Townley E, Dad L, Piscitelli SC, Walsh TJ (2002) Safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole in pediatric patients with oropharyngeal candidiasis. Antimicrob Agents Chemother 46(8):2554–2563PubMedCrossRef

13.

Glasmacher A, Hahn C, Molitor E, Marklein G, Sauerbruch T, Schmidt-Wolf IG (1999) Itraconazole through concentrations in antifungal prophylaxis with six different dosing regimens using hydroxypropyl-beta-cyclodextrin oral solution or coated-pellet capsules. Mycoses 42(11–12):591–600PubMedCrossRef

14.

Pandya NA, Atra AA, Riley U, Pinkerton CR (2003) Role of itraconazole in haematology/oncology. Arch Dis Child 88(3):258–260PubMedCrossRef

15.

Glasmacher A, Molitor E, Hahn C, Bomba K, Ewig S, Leutner C, Wardelmann E, Schmidt-Wolf IG, Mezger J et al (1998) Antifungal prophylaxis with itraconazole in neutropenic patients with acute leukaemia. Leukemia 12(9):1338–1343PubMedCrossRef

16.

Glasmacher A, Prentice AG (2005) Evidence-based review of antifungal prophylaxis in neutropenic patients with haematological malignancies. J Antimicrob Chemother 56(Suppl 1):i23–i32PubMedCrossRef

17.

Prentice AG, Glasmacher A (2005) Making sense of itraconazole pharmacokinetics. J Antimicrob Chemother 56(Suppl 1):i17–i22PubMedCrossRef

18.

Gupta AK, Cooper EA, Ryder JE, Nicol KA, Chow M, Chaudhry MM (2004) Optimal management of fungal infections of the skin, hair, and nails. Am J Clin Dermatol 5(4):225–237PubMedCrossRef

19.

Mondal RK, Singhi SC, Chakrabarti A, MJ (2004) Randomized comparison between fluconazole and itraconazole for the treatment of candidemia in a pediatric intensive care unit: a preliminary study. Pediatr Crit Care Med 5(6):561–565PubMedCrossRef

20.

Singhi SC, Reddy TC, Chakrabarti A (2004) Oral itraconazole in treatment of candidemia in a pediatric intensive care unit. Indian J Pediatr 71(11):973–977PubMed

21.

Groll AH (2002) Itraconazole—perspectives for the management of invasive aspergillosis. Mycoses 45(Suppl 3):48–55PubMed

22.

Castagnola E, Machetti M, Bucci B, Viscoli C (2004) Antifungal prophylaxis with azole derivatives. Clin Microbiol Infect 10(Suppl 1):86–95PubMedCrossRef

23.

Sathiapalan RK, Al-Nasser A, El-Solh H, Al-Mohsen I, Al-Jumaah S (2002) Vincristine–itraconazole interaction: cause for increasing concern. J Pediatr Hematol Oncol 24(7):591PubMedCrossRef

24.

Schmitt C, Perel Y, Harousseau JL, Lemerle S, Chwetzoff E, le Moing JP, Levron JC (2001) Pharmacokinetics of itraconazole oral solution in neutropenic children during long-term prophylaxis. Antimicrob Agents Chemother 45(5):1561–1564PubMedCrossRef

25.

Srivatsan V, Dasgupta AK, Kale P, Datla RR, Soni D, Patel M, Patel R, Mavadhiya C (2004) Simultaneous determination of itraconazole and hydroxyitraconazole in human plasma by high-performance liquid chromatography. J Chromatogr A 1031(1–2):307–313PubMed

26.

Kamaluddin M, McNally P, Breatnach F, O’Marcaigh A, Webb D, O’Dell E, Scanlon P, Butler K, O’Meara A (2001) Potentiation of vincristine toxicity by itraconazole in children with lymphoid malignancies. Acta Paediatr 90(10):1204–1207PubMedCrossRef

27.

Penzak SR, Gubbins PO, Gurley BJ, Wang PL, Saccente M (1999) Grapefruit juice decreases the systemic availability of itraconazole capsules in healthy volunteers. Ther Drug Monit 21(3):304–309PubMedCrossRef

28.

Lange D, Pavao JH, Wu J, Klausner M (1997) Effect of a cola beverage on the bioavailability of itraconazole in the presence of H2 blockers. J Clin Pharmacol 37(6):535–540PubMed

29.

Schmidt LE, Dalhoff K (2002) Food-drug interactions. Drugs 62(10):1481–1502PubMedCrossRef

30.

Litalien C, Theoret Y, Faure C (2005) Pharmacokinetics of proton pump inhibitors in children. Clin Pharmacokinet 44(5):441–466PubMedCrossRef

31.

Steinbach WJ (2005) Antifungal agents in children. Pediatr Clin North Am 52(3):895–915, viiiPubMedCrossRef

32.

Foot AB, Veys PA, Gibson BE (1999) Itraconazole oral solution as antifungal prophylaxis in children undergoing stem cell transplantation or intensive chemotherapy for haematological disorders. Bone Marrow Transplant 24(10):1089–1093PubMedCrossRef

33.

Groll AH, Kolve H (2004) Antifungal agents: in vitro susceptibility testing, pharmacodynamics, and prospects for combination therapy. Eur J Clin Microbiol Infect Dis 23(4):256–270PubMedCrossRef

34.

Maertens J, Boogaerts M (2005) The place for itraconazole in treatment. J Antimicrob Chemother 56(Suppl 1):i33–i38PubMedCrossRef

35.

Warris A, Weemaes CM, Verweij PE (2002) Multidrug resistance in Aspergillus fumigatus. N Engl J Med 347(26):2173–2174PubMedCrossRef

36.

Marr KA, Crippa F, Leisenring W, Hoyle M, Boeckh M, Balajee SA, Nichols WG, Musher B, Corey L (2004) Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood 103(4):1527–1533PubMedCrossRef

37.

Yuan R, Flockhart DA, Balian JD (1999) Pharmacokinetic and pharmacodynamic consequences of metabolism-based drug interactions with alprazolam, midazolam, and triazolam. J Clin Pharmacol 39(11):1109–1125PubMed

38.

Bashir H, Motl S, Metzger ML, Howard SC, Kaste S, Krasin MP, Hudson MM (2006) Itraconazole-enhanced chemotherapy toxicity in a patient with Hodgkin lymphoma. J Pediatr Hematol Oncol 28(1):33–35PubMed

39.

Marr KA, Leisenring W, Crippa F, Slattery JT, Corey L, Boeckh M, McDonald GB (2004) Cyclophosphamide metabolism is affected by azole antifungals. Blood 103(4):1557–1559PubMedCrossRef

Title: Itraconazole prophylaxis in pediatric cancer patients receiving conventional chemotherapy or autologous stem cell transplants
Authors: Arne Simon
Mette Besuden
Sandra Vezmar
Carola Hasan
Dagmar Lampe
Sigrid Kreutzberg
Axel Glasmacher
Udo Bode
Gudrun Fleischhack
Publication date: 01-02-2007
Publisher: Springer-Verlag
Published in: Supportive Care in Cancer / Issue 2/2007
Print ISSN: 0941-4355
Electronic ISSN: 1433-7339
DOI: https://doi.org/10.1007/s00520-006-0125-7

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Abstract

Goal of work

Materials and methods

Results

Conclusion

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