Antifungal therapy strategies in hematopoietic stem-cell transplant recipients: Early treatment options for improving outcomes

Transplantation

Volumn 86, Issue 2, 2008, Pages 183-191

  Chandrasekar, Pranatharthi ^a   Ljungman, Per T ^b  

^a WAYNE STATE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

Author keywords

Azole; Empirical therapy; Prophylaxis

Indexed keywords

AMPHOTERICIN; AMPHOTERICIN B; AMPHOTERICIN B CHOLESTEROL SULFATE; AMPHOTERICIN B LIPID COMPLEX; ANIDULAFUNGIN; ANTIBIOTIC AGENT; ANTIFUNGAL AGENT; CASPOFUNGIN; ECHINOCANDIN; FLUCONAZOLE; ITRACONAZOLE; MICAFUNGIN; PLACEBO; POSACONAZOLE; PYRROLE DERIVATIVE; VORICONAZOLE;

CHEMOPROPHYLAXIS; CLINICAL TRIAL; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG SAFETY; DRUG WITHDRAWAL; GASTROINTESTINAL SYMPTOM; GRAFT RECIPIENT; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HUMAN; LIVER TOXICITY; MORBIDITY; MORTALITY; MYCOSIS; NEPHROTOXICITY; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; UNSPECIFIED SIDE EFFECT; VISUAL HALLUCINATION; ANIMAL; METHODOLOGY; MULTIMODALITY CANCER THERAPY; RISK; RISK FACTOR; TREATMENT OUTCOME;

ANIMALS; ANTIFUNGAL AGENTS; AZOLES; CLINICAL TRIALS AS TOPIC; COMBINED MODALITY THERAPY; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HUMANS; MYCOSES; RISK; RISK FACTORS; TREATMENT OUTCOME;

EID: 49249092755     PISSN: 00411337     EISSN: None     Source Type: Journal    
DOI: 10.1097/TP.0b013e318177de64     Document Type: Review

References (115)

1. Ascioglu S, Rex JH, de Pauw B, et al. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: An international consensus. Clin Infect Dis 2002; 34: 7.
2. Mahfouz T, Anaissie E. Prevention of fungal infections in the immu-nocompromised host. Curr Opin Investig Drugs 2003; 4: 974.
3. Jantunen E, Ruutu P, Niskanen L, et al. Incidence and risk factors for invasive fungal infections in allogeneic BMT recipients. Bone Marrow Transplant 1997; 19: 801.
4. Wald A, Leisenring W, van Burik JA, et al. Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis 1997; 175: 1459.
5. Nucci M. Emerging moulds: Fusarium, Scedosporium and zygomycetes in transplant recipients Curr Opin Infect Dis 2003; 16: 607.
6. Wingard JR. Fungal infections after bone marrow transplant. Biol Blood Marrow Transplant 1999; 5: 55.
7. Marr KA, Carter RA, Boeckh M, et al. Invasive aspergillosis in alloge-neic stem cell transplant recipients: Changes in epidemiology and risk factors. Blood 2002; 100: 4358.
8. Hagen EA, Stern H, Porter D, et al. High rate of invasive fungal infections following nonmyeloablative allogeneic transplantation. Clin Infect Dis 2003; 36: 9.
9. Prentice HG, Kibbler CC, Prentice AG. Towards a targeted, risk-based, antifungal strategy in neutropenic patients. Br J Haematol 2000; 110: 273.
10. Afessa B, Peters SG. Major complications following hematopoietic stem cell transplantation. Semin Resp Crit Care Med 2006; 27: 297.
11. Goodrich JM, Reed EC, Mori M, et al. Clinical features and analysis of risk factors for invasive candidal infection after marrow transplantation. J Infect Dis 1991; 164: 731.
12. Krcmery V, Barnes AJ. Non-albicans candida spp. causing fungaemia: Pathogenicity and antifungal resistance. J Hosp Infect 2002; 50: 243.
13. Marr KA, Carter RA, Crippa F, et al. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002; 34: 909.
14. Chandrasekar P. Riches usher dilemmas: Antifungal therapy in invasive aspergillosis. Biol Blood Marrow Transplant 2005; 11: 77.
15. Nucci M, Marr KA, Queiroz-Telles F, et al. Fusarium infection in he-matopoietic stem cell transplant recipients. Clin Infect Dis 2004; 38: 1237.
16. Ascioglu S, De Pauw BE, Meis JFGM. Prophylaxis and treatment of fungal infections associated with haematological malignancies. Int J Antimicrob Agents 2000; 15: 159.
17. Rickerts V, Loeffler J, Bohme A, et al. Diagnosis of disseminated zygo-mycosis using a polymerase chain reaction assay. Eur J Clin Microbiol Infect Dis 2001; 20: 744.
18. Maertens J, Verhaegen J, Lagrou K, et al. Screening for circulating ga-lactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients: A prospective validation. Blood 2001; 97: 1604.
19. Hope WW, Walsh TJ, Denning DW. Laboratory diagnosis of invasive aspergillosis. Lancet Infect Dis 2005; 5: 609.
20. Verweij PE. Advances in diagnostic testing. Med Mycol 2005; 43: S121.
21. Blot S, De Waele JJ. Critical issues in the clinical management of complicated intra-αbdominal infections. Drugs 2005; 65: 1611.
22. Pappas PG. Immunotherapy for invasive fungal infections: From bench to bedside. Drug Resist Updat 2004; 7: 3.
23. Morrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: A potential risk factor for hospital mortality. Antimicrob Agents Chemother 2005; 49: 3640.
24. Greene RE, Schlamm HT, Oestmann J-W, et al. Imaging findings in acute invasive pulmonary aspergillosis: Clinical significance of the halo sign. Clin Infect Dis 2007; 44: 373.
25. Maertens J, Theunissen K, Verhoef G, et al. Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: A prospective feasibility study. Clin Infect Dis 2005; 41: 1242.
26. Lin M-T, Lu H-C, Chen W-L. Improving efficacy of antifungal therapy by polymerase chain reaction-based strategy among febrile patients with neutropenia and cancer. Clin Infect Dis 2001; 33: 1621.
27. Hughes WT, Armstrong D, Bodey GP, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002; 34: 730.
28. Segal BH, Almyroudis NG, Battiwalla M, et al. Prevention and early treatment of invasive fungal infection in patients with cancer and neutropenia and in stem cell transplant recipients in the era of newer broad-spectrum antifungal agents and diagnostic adjuncts. Clin Infect Dis 2007; 44: 402.
29. Goodman JL, Winston DJ, Greenfield RA, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992; 326: 845.
30. Slavin MA, Osborne B, AdamsR,etal. Efficacy and safety offluconazole prophylaxis for fungal infections after marrow transplantation - A prospective, randomized, double-blind study. J Infect Dis 1995; 171: 1545.
31. Bow EJ, Laverdiere M, Lussier N, et al. Antifungal prophylaxis for severely neutropenic chemotherapy recipients: A meta analysis of randomized-controlled clinical trials. Cancer 2002; 94: 3230.
32. Cornely OA, Bohme A, Buchheidt D, et al. Prophylaxis of invasive fungal infectionsinpatients with hematological malignancies and solid tumors - Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Hematol 2003; 82: S186.
33. Winston DJ, Maziarz RT, Chandrasekar PH,etal. Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term an-tifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients: A multicenter, randomized trial. Ann Intern Med 2003; 138: 705.
34. Marr KA, CrippaF, Leisenring W, et al. Itraconazole versus fluconazole for preventionoffungal infectionsin patients receiving allogeneic stem cell transplants. Blood 2004; 103: 1527.
35. Glasmacher A, Cornely O, Ullmann AJ, et al. An open-label randomized trial comparing itraconazole oral solution with fluconazole oral solution for primary prophylaxis of fungal infections in patients with haematological malignancy and profound neutropenia. J Antimicrob Chemother 2006; 57: 317.
36. Oren I, Rowe JM, Sprecher H, et al. A prospective randomized trial of itraconazole vs fluconazole for the prevention of fungal infections in patients with acute leukemia and hematopoietic stem cell transplant recipients. Bone Marrow Transplant 2006; 38: 127.
37. Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007; 356: 335.
38. van Burik JA, Ratanatharathorn V, Stepan DE, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia inpatients undergoing hematopoietic stem cell transplantation. Clin Infect Dis 2004; 39: 1407.
39. Gallis HA, Drew RH, Pickard WW. Amphotericin B: 30yearsof clinical experience. Rev Infect Dis 1990; 12: 308.
40. Ellis D. Amphotericin B: Spectrum and resistance. J Antimicrob Chemother 2002; 49: 7.
41. Dannaoui E, Meletiadis J, Mouton JW, et al. In vitro susceptibilities of Zygomycetes to conventional and new antifungals. J Antimicrob Chemother 2003; 51: 45.
42. EORTC International Antimicrobial Therapy Cooperative Group. Empiric antifungal therapy in febrile granulocytopenic patients. Am J Med 1989; 86: 668.
43. Prentice HG, Hann IM, Herbrecht R, et al. A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients. Br J Haematol 1997; 98: 711.
44. Deray G. Amphotericin B nephrotoxicity. J Antimicrob Chemother 2002; 49: 37.
45. White MH, Bowden RA, Sandler ES, et al. Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia. Clin Infect Dis 1998; 27: 296.
46. Walsh TJ, Finberg RW, Arndt C, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med 1999; 340: 764.
47. Kelsey SM, Goldman JM, McCann S, et al. Liposomal amphotericin (AmBisome) in the prophylaxis of fungal infections in neutropenic patients: A randomised, double-blind, placebo-controlled study. Bone Marrow Transplant 1999; 23: 163.
48. Tollemar J, Ringden O, Andersson S, et al. Randomized double-blind study of liposomal amphotericin B (Ambisome) prophylaxis of invasive fungal infections in bone marrow transplant recipients. Bone Marrow Transplant 1993; 12: 577.
49. Perea S, Patterson TF. Antifungal resistance in pathogenic fungi. Clin Infect Dis 2002; 35: 1073.
50. Gallagher JC, MacDougall C, Ashley DES, et al. Recent advances in antifungal pharmacotherapy for invasive fungal infections. Expert Rev Anti Infect Ther 2004; 2: 253.
51. Bedini A, Venturelli C, Mussini C, et al. Epidemiology of candidaemia and antifungal susceptibility patterns in an Italian tertiary-care hospital. Clin Microbiol Infect 2006; 12: 75.
52. Pfaller MA, Messer SA, Hollis RJ, et al. Trends in species distribution and susceptibility to fluconazole among blood stream isolates of Candida species in the United States. Diagn Microbiol Infect Dis 1999; 33: 217.
53. Hajjeh RA, Sofair AN, Harrison LH, et al. Incidence of bloodstream infections due to Candida species and in vitro susceptibilities of isolates collected from 1998 to 2000 in a population-based active surveillance program. J Clin Microbiol 2004; 42: 1519.
54. Winston DJ, Hathorn JW, Schuster MG, et al. A multicenter, randomized trial of fluconazole versus amphotericin B for empiric antifungal therapy of febrile neutropenic patients with cancer. Am J Med 2000; 108: 282.
55. Viscoli C,Castagnola E, Van Lint MT,etal. Fluconazole versus ampho-tericin B as empirical antifungal therapy of unexplained fever in gran-ulocytopenic cancer patients: A pragmatic, multicentre, prospective and randomised clinical trial. Eur J Cancer 1996; 32A: 814.
56. Stemmer SM, Maor Y, Hardan I. Oral fluconazole for empiric treatment of prolonged fever in neutropenic patients: Prospective study in 250 consecutive patients after stem cell transplantation. Am J Clin Oncol 2004; 27: 328.
57. Rotstein C, Bow EJ, Laverdiere M, et al. Randomized placebo-controlled trial of fluconazole prophylaxis for neutropenic cancer patients: Benefit basedonpurpose and intensity ofcytotoxic therapy.Clin Infect Dis 1999; 28: 331.
58. Sheehan DJ, Hitchcock CA, Sibley CM. Current and emerging azole antifungal agents. Clin Microbiol Rev 1999; 12: 40.
59. Arikan S, Lozano-Chiu M, Paetznick V, et al. Microdilution susceptibility testing of amphotericin B, itraconazole, and voriconazole against clinical isolates of Aspergillus and Fusarium species. J Clin Microbiol 1999; 37: 3946.
60. De Beule K, Van Gestel J. Pharmacology of itraconazole. Drugs 2001; 61: 27.
61. Negroni R, Arechavala AI. Itraconazole: Pharmacokinetics and indications. Arch Med Res 1993; 24: 387.
62. Chryssanthou E, Cherif H, Petrini B, et al. Surveillance of triazole susceptibility of colonizing yeasts in patients with haematological malignancies. Scand J Infect Dis 2004; 36: 855.
63. Barone JA, Moskovitz BL, Guarnieri J,etal. Enhanced bioavailability of itraconazole in hydroxypropyl-beta-cyclodextrin solution versus capsules in healthy volunteers. Antimicrob Agents Chemother 1998; 42: 1862.
64. Prentice AG, Glasmacher A. Making sense of itraconazole pharmacokinetics. J Antimicrob Chemother 2005; 56: i17.
65. Trotman RL, Williamson JC, Shoemaker DM, et al. Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy. Clin Infect Dis 2005; 41: 1159.
66. Boogaerts M, Winston DJ, Bow EJ, et al. Intravenous and oral itracon-azole versus intravenous amphotericin B deoxycholate as empirical an-tifungal therapy for persistent fever inneutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy: A randomized, controlled trial. Ann Intern Med 2001; 135: 412.
67. Glasmacher A, Prentice A, Gorschluter M, et al. Itraconazole prevents invasive fungal infections in neutropenic patients treated for hematologic malignancies: Evidence from a meta-αnalysis of 3,597 patients. J Clin Oncol 2003; 21: 4615.
68. Harousseau JL, Dekker AW, Stamatoullas-BastardA,et al. Itraconazole oral solution for primary prophylaxis of fungal infections in patients with hematological malignancy and profound neutropenia:Arandom-ized, double-blind, double-placebo, multicenter trial comparing itra-conazole and amphotericin B. Antimicrob Agents Chemother 2000; 44: 1887.
69. Morgenstern GR, Prentice AG, Prentice HG, et al. A randomized controlled trial of itraconazole versus fluconazole for the prevention of fungal infections in patients with haematological malignancies. Br J Haematol 1999; 105: 901.
70. Boucher HW, Groll AH, Chiou CC, et al. Newer systemic antifungal agents: Pharmacokinetics, safety and efficacy. Drugs 2004; 64: 1997.
71. von Mach MA, Burhenne J, Weilemann LS. Accumulation of the solvent vehicle sulphobutylether beta cyclodextrin sodium in critically ill patients treated with intravenous voriconazole under renal replacement therapy. BMC Clin Pharmacol 2006; 6: 6.
72. Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002; 346: 225.
73. Powers JH, Dixon CA, Goldberger MJ. Voriconazole versus liposomal amphotericin B in patients with neutropenia and persistent fever [letter]. N Engl J Med 2002; 346: 289.
74. Vehreschild JJ, Bohme A, Buchheidt D, et al. A double-blind trial on prophylactic voriconazole (VRC) or placebo during induction chemotherapy for acute myelogenous leukaemia (AML). J Infect 2007; 55:445.
75. Siwek GT, Pfaller MA, Polgreen PM, et al. Incidence of invasive aspergillosis among allogeneic hematopoietic stem cell transplant patients receiving voriconazole prophylaxis. Diagn Microbiol Infect Dis 2006; 55: 209.
76. Wingard JR, Carter SL, Walsh TJ, et al. Results of a randomized, double-blind trial of fluconazole (FLU) vs. voriconazole (VORI) for the prevention of invasive fungal infections (IF) in 600 allogeneic blood and marrow transplant (BMT) patients. 49th Annual Meeting and Exposition of the American Society of Hematology, December 8, 2007.
77. Siwek GT, Dodgson KJ, de Magalhaes-Silverman M, et al. Invasive zygomycosis in hematopoietic stem cell transplant recipients receiving voriconazole prophylaxis. Clin Infect Dis 2004; 39: 584.
78. Imhof A, Balajee SA, Fredricks DN, et al. Breakthrough fungal infections in stem cell transplant recipients receiving voriconazole. Clin Infect Dis 2004; 39: 743.
79. Marty FM, Cosimi L, Baden LR. Breakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants. N Engl J Med 2004; 350: 950.
80. Vigouroux S, Morin O, Moreau P, et al. Zygomycosis after prolonged use of voriconazole in immunocompromised patients with hematologic disease: Attention required. Clin Infect Dis 2005; 40: e35.
81. Cordonnier C, Maury S, Pautas C, et al. Secondary antifungal prophylaxis with voriconazole to adhere to scheduled treatment in leukemic patients and stem cell transplant recipients. Bone Marrow Transplant 2004; 33: 943.
82. Martino R, Parody R, Fukuda T, et al. Impact of the intensity of the pretransplantation conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic hematopoietic stem cell transplantation: A retrospective survey of the Infectious Diseases Working Party of the European Group for blood and marrow transplantation. Blood 2006; 108: 2928.
83. Sabatelli F, Patel R, Mann PA, et al. In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts. Antimicrob Agents Chemother 2006; 50: 2009.
84. Schering Corporation. NOXAFIL® (posaconazole) Oral Suspension. Kenilworth, NJ, Schering Corporation 2006.
85. Wexler D, Courtney R, Richards W, et al. Effect of posaconazole on cytochrome P450 enzymes: A randomized, open-label, two-way crossover study. Eur J Pharm Sci 2004; 21: 645.
86. Ullmann AJ, Cornely OA, Burchardt A, et al. Pharmacokinetics, safety, and efficacy of posaconazole in patients with persistent febrile neutropenia or refractory invasive fungal infection. Antimicrob Agents Chemother 2006; 50: 658.
87. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007; 356: 348.
88. Nakai T, Uno J, Ikeda F, et al. In vitro antifungal activity of micafungin (FK463) against dimorphic fungi: Comparison of yeast-like and mycelial forms. Antimicrob Agents Chemother 2003; 47: 1376.
89. Yanada M, Kiyoi H, Murata M, et al. Micafungin, a novel antifungal agent, as empirical therapy in acute leukemia patients with febrile neutropenia. Intern Med 2006; 45: 259.
90. Cornely OA, Ullmann AJ, Karthaus M. Choosing a study population for the evaluation of antifungal prophylaxis [letter]. Clin Infect Dis 2005; 40: 1699.
91. Espinel-Ingroff A. Comparison of in vitro activities of the new triazole SCH56592 and the echinocandins MK-0991 (L-743,872) and LY303366 against opportunistic filamentous and dimorphic fungi and yeasts. J Clin Microbiol 1998; 36: 2950.
92. Walsh TJ, Teppler H, Donowitz GR, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med 2004; 351: 1391.
93. Mattiuzzi GN, Alvarado G, Giles FJ, et al. Open-label, randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies. Antimicrob Agents Chemother 2006; 50: 143.
94. Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin versus flucon-azole for invasive candidiasis. N Engl J Med 2007; 356: 2472.
95. Benjamin DK Jr, Driscoll T, Seibel NL, et al. Safety and pharmacoki-netics of intravenous anidulafungin in children with neutropenia at high risk for invasive fungal infections. Antimicrob Agents Chemother 2006; 50: 632.
96. van der Horst CM, Saag MS, Cloud GA, et al. Treatment of crypto-coccal meningitis associated with the acquired immunodeficiency syndrome: National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med 1997; 337: 15.
97. de Gans J, Portegies P, Tiessens G, et al. Itraconazole compared with amphotericin B plus flucytosine in AIDS patients with cryptococcal meningitis. AIDS 1992; 6: 185.
98. Marr KA, Boeckh M, Carter RA, et al. Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis2004; 39: 797.
99. Maertens J, Glasmacher A, Herbrecht R, et al. Multicenter, noncom-parative study of caspofungin in combination with other antifungals as salvage therapy in adults with invasive aspergillosis. Cancer 2006; 107: 2888.
100. Cesaro S, Toffolutti T, Messina C, et al. Safety and efficacy of caspofun-gin and liposomal amphotericin B, followed by voriconazole in young patients affected by refractory invasive mycosis. Eur J Haematol 2004; 73: 50.
101. Steinbach WJ, Stevens DA, Denning DW. Combination and sequential antifungal therapy for invasive aspergillosis: Review of published in vitro andinvivo interactions and 6281 clinical cases from 1966to2001. Clin Infect Dis2003; 37: S188.
102. Chandrasekar P. Selection criteria for antifungals: The right patients and the right reasons. Int J Antimicrob Agents 2006; 27: 17.
103. Dannaoui E, Meis JF, Loebenberg D, et al. Activity of posaconazole in treatment of experimental disseminated zygomycosis. Antimicrob Agents Chemother 2003; 47: 3647.
104. van Burik J-AH, Hare RS, Solomon HF, et al. Posaconazole is effective as salvage therapyin zygomycosis:Aretrospective summary of 91cases. Clin Infect Dis2006; 42: e61.
105. Trifilio S, Pennick G, Pi J, et al. Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients. Cancer 2007; 109: 1532.
106. Trifilio S, Ortiz R, Pennick G, et al. Voriconazole therapeutic drug monitoring in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 2005; 35: 509.
107. Pascual A, Calandra T, Bolay S, et al. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis2008; 46: 201.
108. Smith J, Safdar N, Knasinski V, et al. Voriconazole therapeutic drug monitoring. Antimicrob Agents Chemother 2006; 50: 1570.
109. Trifilio S, Singhal S, Williams S, et al. Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole. Bone Marrow Transplant 2007; 40: 451.
110. Walsh TJ, RaadI,Patterson TF,etal. Treatmentofinvasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: An externally controlled trial. Clin Infect Dis2007; 44: 2.
111. Munoz P, Burillo A, Bouza E. Mold infections after solid organ transplantation. In: Bowden RA, Ljungman P, Paya CV, eds. Transplant infections. New York: Lippincott Williams & Wilkins 2006, p 483.
112. Singh N. Fungal infections in the recipients of solid organ transplantation. Infect Dis Clin North Am 2003; 17: 113.
113. CrucianiM,MengoliC,MalenaM, etal. Antifungal prophylaxisinliver transplant patients: A systematic review and meta-αnalysis. Liver Transplant 2006; 12: 850.
114. Heathcote J, Main J. Treatment of hepatitis C. J Viral Hepat 2005; 12: 223.
115. Singh N, Paterson DL. Aspergillus infections in transplant recipients. Clin Microbiol Rev 2005; 18: 44.