Prävention von Pilzinfektionen bei Kindern und Jugendlichen mit neoplastischen Erkrankungen

Zusammenfassung.

Opportunistische Pilzinfektionen sind eine wichtige Ursache von Morbidität und Mortalität krebskranker Kinder und Jugendlicher. Betroffen sind vor allem Patienten mit intensiv zytostatisch behandelten hämatologischen Neoplasien, allogener hämatopoetischer Stammzelltransplantation und aplastischer Anämie. Die Inzidenz invasiver Pilzinfektionen in diesen Populationen beträgt 10 bis 25 % trotz empirischer antimykotischer Therapie, und die unbereinigte Mortalität liegt in Abhängigkeit vom Erreger zwischen 50 und 75 %. Präventive Interventionen einschließlich der Chemoprophylaxe mit antimykotischen Substanzen sind daher gerechtfertigt und auch grundsätzlich angezeigt. Eine wirksame Chemoprophylaxe invasiver Candida-Infektionen mit langanhaltendem Effekt auf die Überlebenswahrscheinlichkeit wurde bei Patienten mit allogener Knochenmarktransplantation nachgewiesen. Bei anderen Hochrisikopatienten ist ihr Nutzen weniger eindeutig, und eine effektive Chemoprophylaxe invasiver Aspergillus-Infektionen ist bislang nicht durch adäquate klinische Studien belegt. Die vorliegende Arbeit gibt eine Übersicht über die Epidemiologie opportunistischer invasiver Pilzinfektionen bei Kindern und Jugendlichen mit bösartigen Erkrankungen bzw. Stammzelltransplantation sowie die derzeitigen Ansätze der Chemoprophylaxe und enthält Empfehlungen zu Indikationen und Modalitäten der antimykotischen Chemoprophylaxe und allgemeinen Infektionskontrolle auf der Basis der publizierten Literatur.

Opportunistic mycoses have emerged as important causes for morbidity and mortality in pediatric cancer patients, particularly in those with intensively treated hematological malignancies, allogeneic hematopoetic stem cell transplantation, and aplastic anemia. The incidence of invasive fungal infections in these settings may range from 10 to 25 % despite empirical antifungal therapy with an overall case fatality rate of up to 50 and 75 % depending on the organism. Preventive interventions are thus warranted, including but not limited to chemoprophylaxis with antifungal agents. Effective chemoprophylaxis of invasive Candida infections with a long-term benefit for overall survival has been demonstrated in patients with allogeneic bone marrow transplantation. However, its benefit in other high-risk populations is less well established, and a clearly effective approach to chemoprophylaxis for invasive Aspergillus infections has not been documented in appropriately designed clinical trials. This article reviews epidemiology and current approaches to chemoprophylaxis of opportunistic invasive fungal infections in children and adolescents with cancer and/or stem cell transplantation, and provides evidence-based guidelines for indications and modalities of antifungal prophylaxis and antifungal infection control measures in this population.

Schlüsselwörter

Maligne Erkrankungen - Stammzelltransplantation - Mykosen - Candida - Aspergillus - Prophylaxe - Fluconazol - Itraconazol - Amphotericin - Kinder

Key words

Cancer - stem cell transplantation - mycoses - Candida - Aspergillus - prophylaxis - fluconazole - itraconazole - amphotericin - children

Literatur

• 001 Abbasi  S, Shenep  J L, Hughes  W T, Flynn  P M. Aspergillosis in children with cancer: A 34-year experience.  Clin Infect Dis. 1999;;  29 1210-1219
• 002 Allen  S D, Sorensen  K N, Nejdl  M J, Durrant  C, Proffit  R T. Prophylactic efficacy of aerosolized liposomal (AmBisome) and non-liposomal (Fungizone) amphotericin B in murine pulmonary aspergillosis.  J Antimicrob Chemother. 1994;;  34 1001-1013
• 003 Allo  M, Miller  J, Townsend  T, Tan  C. Primary cutaneous aspergillosis associated with Hickman intravenous catheters.  N Engl J Med. 1987;;  315 1105-1113
• 004 Anaissie  E. Opportunistic mycoses in the immunocompromised host: ex-perience at a cancer center and review.  Clin Infect Dis. 1992;;  14 (Suppl 1) S43-53
• 005 Anaissie  E J, Darouiche  R O, Abi-Said  D, Uzun  O, Mera  J, Gentry  L O et al. Management of invasive candidal infections: results of a prospective, randomized, multicenter study of fluconazole versus amphotericin B and review of the literature.  Clin Infect Dis. 1996;;  23 964-972
• 006 Anaissie  E J, Kontoyiannis  D P, Huls  C, Vartivarian  S E, Karl  C, Prince  R A et al. Safety, plasma concentrations, and efficacy of high-dose fluconazole in invasive mold infections.  J Infect Dis. 1995;;  172 599-602
• 007 Anaissie  E J, Rex  J H, Uzun  O, Vartivarian  S. Predictors of adverse outcome in cancer patients with candidemia.  Am J Med. 1998;;  104 238-245
• 008 Anaissie  E J, Stratton  S L, Summerbell  R C, Monson  T P, Rex  J H, Walsh  T J. Aspergillus species aerosols in hospitals: showering as a potential source of exposure abstr. 1908, p. 578. In: Program and Abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington DC; 1999:
• 009 Antifungal Antibiotics .Itraconazole. In: McEvoy GK (ed). American Hospital Formulatory Service Drug Information, chapter 8:12.04. American Society of Health-System Pharmacists Inc, Bethesda MD; 2000:
• 010 Barbaro  G, Barbarini  G, Di Lorenzo  G. Fluconazole compared with itraconazole in the treatment of esophageal candidiasis in AIDS patients: a double-blind, randomized, controlled clinical study.  Scand J Infect Dis. 1995;;  27 613-617
• 011 Barone  J A, Moskovitz  B L, Guarnieri  J, Hassell  A E, Colaizzi  J L, Bierman  R H, Jessen  L. Enhanced bioavailability of itraconazole in hydroxypropyl-beta-cyclodextrin solution versus capsules in healthy volunteers.  Antimicrob Agents Chemother. 1998;;  42 1862-1865
• 012 Berenguer  J, Ali  N M, Allende  M C, Lee  J, Garrett  K, Battaglia  S et al. Itraconazole for experimental pulmonary aspergillosis: comparison with amphotericin B, interaction with cyclosporin A, and correlation between therapeutic response and itraconazole concentrations in plasma.  Antimicrob Agents Chemother. 1994;;  38 1303-1308
• 013 Besnard  M, Hartmann  O, Valteau-Couanet  D, Robert  M C, Brugieres  L, Lemerle  J. Systemic Candida infection in pediatric BM autotransplantation: clinical signs, outcome and prognosis.  Bone Marrow Transplant. 1993;;  11 465-470
• 014 Beyer  J, Barzen  G, Risse  G, Weyer  C, Miksits  K, Dullenkopf  K et al. Aerosol amphotericin B for prevention of invasive pulmonary aspergillosis.  Antimicrob Agents Chemother. 1993;;  37 1367-1369
• 015 Beyer  J, Schwartz  S, Heinemann  V, Siegert  W. Strategies in prevention of invasive pulmonary aspergillosis in immunosuppressed or neutropenic patients.  Antimicrob Agents Chemother. 1994;;  38 911-917
• 016 Bjerke  J W, Meyers  J D, Bowden  R A. Hepatosplenic candidiasis - a contraindication to marrow transplantation?.  Blood. 1994;;  84 2811-2814
• 017 Bodey  G P, Anaissie  E J, Elting  L S, Estey  E, O'Brien  S, Kantarjian  H. Antifungal prophylaxis during remission induction therapy for acute leukemia fluconazole versus intravenous amphotericin B.  Cancer. 1994 15;;  73 2099-2106
• 018 Bodey  G P. Fungal infections complicating acute leukemia.  J Chronic Dis. 1966;;  19 667-687
• 019 Bodey  G P. The emergence of fungi as major hospital pathogens.  J Hosp Infect. 1988;;  11 Suppl A 411-426
• 020 Böhme  A, Just-Nübling  G, Bergmann  L, Shah  P M, Stille  W, Hoelzer  D. Itraconazole for prophylaxis of systemic mycoses in neutropenic patients with haematological malignancies.  J Antimicrob Chemother. 1996;;  38 953-961
• 021 Boogaerts  M A, Verhoef  G E, Zachee  P, Demuynck  H, Verbist  L, De Beule  K. Antifungal prophylaxis with itraconazole in prolonged neutropenia: correlation with plasma levels.  Mycoses. 1989;;  32 Suppl 1 103-108
• 022 Brammer  K W, Coates  P E. Pharmacokinetics of fluconazole in pediatric patients.  Eur J Clin Microbiol Infect Dis. 1994;;  13 325-329
• 023 Caillot  D, Bassaris  H, Seifert  W F, van de Velde  V, Woestenborghs  R, Chwetzoff  E et al. Efficacy, safety, and pharmacokinetics of intravenous followed by oral itraconazole in patients with invasive pul-monary aspergillosis. In: Abstracts of the 39th International Conference on Antimicrobial Agents and Chemotherapy, abstr. 1646, p. 575. American Society for Microbiology, Washington DC; 1999:
• 024 Carillo-Munoz  A J, Quindos  G, Tur  C, Ruesga  M T, Miranda  Y, del Valle  O et al. In vitro antifungal activity of liposomal nystatin in comparison with nys-tatin, amphotericin B cholesteryl sulphate, liposomal amphotericin B, am-photericin B lipid complex, amphotericin B deoxycholate, fluconazole and itraconazole.  J Antimicrob Chemother. 1999;;  4 397-401
• 025 Centers for Disease Control and Prevention .Guidelines for prevention of nosocomial pneumonia. MMWR Morb Mortal Wkly Rep 1997; 46 (RR-1): 1-79
• 026 Centers for Disease Control and Prevention .Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Morb Mortal Wkly Rep 2000; 49 (RR-10): 1-95
• 027 Chiou  C C, Groll  A H, Walsh  T J. New drugs and novel targets for treatment of invasive fungal infections in patients with cancer.  Oncologist. 2000;;  5 120-135
• 028 Cicogna  C E, White  M H, Bernard  E M, Ishimura  T, Sun  M, Tong  W P, Armstrong  D. Efficacy of prophylactic aerosol amphotericin B lipid complex in a rat model of pulmonary aspergillosis.  Antimicrob Agents Chemother. 1997;;  41 259-261
• 029 Conneally  E, Cafferkey  M T, Daly  P A, Keane  C T, McCann  S R. Nebulized amphotericin B as prophylaxis against invasive aspergillosis in granulocytopenic patients.  Bone Marrow Transplant. 1990;;  5 403-406
• 030 Crippa  F, Corey  L, Leichsenring  Q, Hoyle  M, Boeckh  M, Marr  K. Administration of itraconazole for antifungal prophylaxis in stem cell transplant recipients: levels and drug interactions. In: Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, abstr. 850, page 25. American Society for Microbiology, Washington DC; 2000:
• 031 Cushing  D, Bustamante  C, Devlin  A, Finley  R, Wade  J. Aspergillus infection prophylaxis: amphotericin B nasal spray, a double blind trial. In: Abstracts of the 31st Interscience Conference on Antimicrobial Agents and Chemotherapy, abstr. 737, page 222. American Society for Microbiology, Washington DC; 1991:
• 032 Dannaoui  E, Borel  E, Monier  M F, Piens  M A, Picot  S, Persat  F. Acquired itraconazole resistance in Aspergillus fumigatus.  J Antimicrob Chemother. 2001;;  47 333-340
• 033 De Beule  K. Itraconazole: Pharmacology, clinical experience and future development.  Int J Antimicrobial Agents. 1996;;  6 175-181
• 034 De Laurenzi  A, Matteocci  A, Lanti  A, Pescador  L, Blandino  F, Papetti  C. Amphotericin B prophylaxis against invasive fungal infections in neutropenic patients: a single center experience from 1980 to 1995.  Infection. 1996;;  24 361-366
• 035 De Repentigny  L, Ratelle  J, Leclerc  J M, Cornu  G, Sokal  E M, Jacqmin  P, De Beule  K. Repeated-dose pharmacokinetics of an oral solution of itraconazole in infants and children.  Antimicrob Agents Chemother. 1998;;  42 404-408
• 036 Denning  D W, Lee  J Y, Hostetler  J S, Pappas  P, Kauffman  C A, Dewsnup  D H et al. NIAID Mycoses Study Group Multicenter Trial of Oral Itraconazole Therapy for Invasive Aspergillosis.  Am J Med. 1994;;  97 135-144
• 037 Denning  D W, Marinus  A, Cohen  J, Spence  D, Herbrecht  R, Pagano  L et al. An EORTC multicentre prospective survey of invasive aspergillosis in haemato-logical patients: diagnosis and therapeutic outcome. EORTC Invasive Fungal Infections Cooperative Group.  J Infect. 1998;;  37 173-180
• 038 Denning  D W, Radford  S A, Oakley  K L, Hall  L, Johnson  E M, Warnock  D W. Correlation between in-vitro susceptibility testing to itraconazole and in-vivo outcome of Aspergillus fumigatus infection.  J Antimicrob Chemother. 1997;;  40 401-414
• 039 Denning  D W. Invasive aspergillosis.  Clin Infect Dis. 1998;;  26 781-805
• 040 Diamond  R D. Invasive aspergillosis: host defenses.  Recent Results Cancer Res. 1993;;  132 109-115
• 041 Dick  J D, Merz  W G, Saral  R. Incidence of polyene-resistant yeasts recovered from clinical specimens.  Antimicrob Agents Chemother. 1980;;  18 158-163
• 042 Dixon  D M, Casadevall  A, Klein  B, Mendoza  L, Travassos  L, Deepe  G S. Development of vaccines and their use in the prevention of fungal infections.  Med Mycol. 1998;;  36 Suppl 1 57-67
• 043 Dubois  J, Bartter  T, Gryn  J, Pratter  M R. The physiologic effects of inhaled amphotericin B.  Chest. 1995;;  108 750-753
• 044 Einsele  H, Hebart  H, Roller  G, Löffler  J, Rothenhofer  I, Müller  C A et al. Detection and identification of fungal pathogens in blood by using molecular probes.  J Clin Microbiol. 1997;;  35 1353-1360
• 045 Ellis  M E, Clink  H, Ernst  P, Halim  M A, Padmos  A, Spence  D et al. Controlled study of fluconazole in the prevention of fungal infections in neutropenic patients with haematological malignancies and bone marrow transplant recipients.  Eur J Clin Microbiol Infect Dis. 1994;;  13 3-11
• 046 Erjavec  Z, Woolthuis  G M, de Vries-Hospers  H G, Sluiter  W J, Daenen  S M, de Pauw  B, Halie  M R. Tolerance and efficacy of Amphotericin B inhalations for prevention of invasive pulmonary aspergillosis in haematological patients.  Eur J Clin Microbiol Infect Dis. 1997;;  16 364-368
• 047 Ezdinli  E Z, O'Sullivan  D D, Wasser  L P, Kim  U, Stutzman  L. Oral amphotericin for candidiasis in patients with hematologic neoplasms. An autopsy study.  JAMA. 1979;;  242 258-260
• 048 Finlay  P M, Richardson  M D, Robertson  A G. A comparative study of the efficacy of fluconazole and amphotericin B in the treatment of oropharyngeal candidosis in patients undergoing radiotherapy for head and neck tumours.  Br J Oral Maxillofac Surg. 1996;;  34 23-25
• 049 Flynn  P M, Cunningham  C K, Kerkering  T, San Jorge  A R, Peters  V B, Pitel  P A et al. Oropharyngeal candidiasis in immunocompromised children: a randomized, multicenter study of orally administered fluconazole suspension versus nystatin. The Multicenter Fluconazole Study Group.  J Pediatr. 1995;;  127 322-328
• 050 Foot  A B, Veys  P A, Gibson  B E. Itraconazole oral solution as antifungal prophylaxis in children undergoing stem cell transplantation or intensive chemotherapy for haematological disorders.  Bone Marrow Transplant. 1999;;  24 1089-1093
• 051 Glasmacher  A, Hahn  C, Molitor  E, Marklein  G, Sauerbruch  T, Schmidt-Wolf  I G. Itraconazole through concentrations in antifungal prophylaxis with six different dosing regimens using hydroxypropyl-beta-cyclodextrin oral solution or coated-pellet capsules.  Mycoses. 1999;;  42 591-600
• 052 Glasmacher  A, Hahn  C, Molitor  E, Sauerbruch  T, Marklein  G, Schmidt-Wolf  I GH. Definition of itraconazole target concentration for antifungal prophylaxis. In: Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, abstr. 700, page 363. American Society for Microbiology, Washington DC; 2000:
• 053 Glasmacher  A, Molitor  E, Hahn  C, Bomba  K, Ewig  S, Leutner  C et al. Antifungal prophylaxis with itraconazole in neutropenic patients with acute leukaemia.  Leukemia. 1998;;  12 1338-1343
• 054 Goldman  M, Cloud  G A, Smedema  M, LeMonte  A, Connolly  P, McKinsey  D S et al. Does long-term itraconazole prophylaxis result in in vitro azole resistance in mucosal Candida albicans isolates from persons with advanced human immunodeficiency virus infection?.  Antimicrob Agents Chemother. 2000;;  44 1585-1587
• 055 Goodman  J L, Winston  D J, Greenfield  R A, Chandrasekar  P H, Fox  B, Kaizer  H et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation.  N Engl J Med. 1992;;  326 845-851
• 056 Goodrich  J M, Reed  E C, Mori  M, Fisher  L D, Skerrett  S, Dandliker  P S et al. Clinical features and analysis of risk factors for invasive Candidal infection after marrow transplantation.  J Infect Dis. 1991;;  164 731-740
• 057 Grant  S M, Clissold  S P. Fluconazole. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses.  Drugs. 1990;;  39 877-916
• 058 Grant  S M, Clissold  S P. Itraconazole. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in superficial and systemic mycoses.  Drugs. 1989;;  37 310-344
• 059 Griese  M, Schams  A, Lohmeier  K P. Amphotericin B and pulmonary surfactant.  Eur J Med Res. 1998;;  3 383-386
• 060 Groll  A H, Just-Nuebling  G, Kurz  M, Mueller  C, Nowak-Goettl  U, Schwabe  D et al. Fluconazole versus nystatin in the prevention of Candida infections in children and adolescents undergoing remission induction or consolidation chemotherapy for cancer.  J Antimicrob Chemother. 1997;;  40 855-862
• 061 Groll  A H, Kurz  M, Schneider  W, Witt  V, Schmidt  H, Schneider  M et al. Five-year survey of invasive aspergillosis in a pediatric cancer center: Incidence, clinical presentation, management, and long-term survival.  Mycoses. 1999;;  42 431-442
• 062 Groll  A H, Mickiene  D, McEvoy  M, Dad  L, Townley  E, Piscitelli  S, Wood  L, Walsh  T J. Pharmacokinetics and pharmacodynamics of cyclodextrin itraconazole in pediatric patients with HIV infection and oropharyngeal candidiasis. In: Abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, abstr. 1647, page 575. American Society for Microbiology, Washington DC; 1999:
• 063 Groll  A H, Mueller  F MC, Piscitelli  S C, Walsh  T J. Lipid formulations of Amphotericin B: Clinical perspectives for the management of invasive fungal infections in children with cancer.  Klin Pädiatr. 1998;;  210 264-273
• 064 Groll  A H, Mueller  F MC. Fortschritte in Praevention und Therapie infektioeser Komplikationen bei Kindern und Jugendlichen mit neoplastischen Erkrankungen.  Klin Pädiatr. 1998;;  210 106-114
• 065 Groll  A H, Piscitelli  S C, Walsh  T J. Antifungal pharmacodynamics. Concentration-effect relationships in vitro and in vivo. Pharmacotherapy (in press):
• 066 Groll  A H, Piscitelli  S C, Walsh  T J. Clinical pharmacology of systemic antifungal agents: a comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development.  Adv Pharmacol. 1998;;  44 343-500
• 067 Groll  A H, Shah  P M, Mentzel  C, Schneider  M, Just-Nuebling  G, Huebner  K. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital.  J Infect. 1996;;  33 23-32
• 068 Groll  A H, Walsh  T J. Antifungal Triazoles. In: Yu VL, Merigan TC, Barriere S (eds). Antimicrobial Chemotherapy and Vaccines. Williams and Wilkins, Baltimore; 1998;: pp 1158-1170
• 069 Groll  A H, Walsh  T J. Potential new antifungal agents.  Curr Opin Infect Dis. 1997;;  10 449-458
• 070 Grossmann  M E, Fithian  E C, Behrens  C, Bissinger  J, Fracaro  M, Neu  H C. Primary cutaneous aspergillosis in six leukemic children.  J Am Acad Dermatol. 1985;;  12 313-318
• 071 Gryn  J, Goldberg  J, Johnson  E, Siegel  J, Inzerillo  J. The toxicity of daily inhaled amphotericin B.  Am J Clin Oncol. 1993;;  16 43-46
• 072 Guiot  H F, Fibbe  W E, van't Wout  J W. Risk factors for fungal infection in pa-tients with malignant hematologic disorders: implications for empirical therapy and prophylaxis.  Clin Infect Dis. 1994;;  18 525-532
• 073 Hansen  J A, Gooley  T A, Martin  P J, Appelbaum  F, Chauncey  T R, Clift  R A et al. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia.  N Engl J Med. 1998;;  338 962-968
• 074 Harousseau  J L, Dekker  A W, Stamatoullas-Bastard  A, Fassas  A, Linkesch  W, Gouveia  J et al. Itraconazole oral solution for primary prophylaxis of fungal infections in patients with hematological malignancy and profound neutropenia: a randomized, double-blind, double-placebo, multicenter trial comparing itraconazole and amphotericin B.  Antimicrob Agents Chemother. 2000;;  44 1887-1893
• 075 Hertenstein  B, Kern  W V, Schmeiser  T, Stefanic  M, Bunjes  D, Wiesneth  M et al. Low incidence of invasive fungal infections after bone marrow transplantation in patients receiving amphotericin B inhalations during neutropenia.  Ann Hematol. 1994;;  68 21-26
• 076 Hiemenz  J W, Walsh  T J. Lipid formulations of amphotericin B: recent progress and future directions.  Clin Infect Dis. 1996;;  22 Suppl 2 S133-144
• 077 Huijgens  P C, Simoons-Smit  A M, van Loenen  A C, Prooy  E, van Tinteren  H, Ossenkoppele  G J, Jonkhoff  A R. Fluconazole versus itraconazole for the prevention of fungal infections in haematooncology.  J Clin Pathol. 1999;;  52 376-380
• 078 Janknegt  R, de Marie  S, Bakker-Woudenberg  I A, Crommelin  D J. Liposomal and lipid formulations of amphotericin B. Clinical pharmacokinetics.  Clin Pharmacokinet. 1992;;  23 279-291
• 079 Jarque  I, Saavedra  S, Martin  G, Peman  J, Perez Belles  C, Sanz  M A. Delay of onset of candidemia and emergence of Candida krusei fungemia in hematologic patients receiving prophylactic fluconazole.  Haematologica. 2000;;  85 441-443
• 080 Jeffery  G M, Beard  M E, Ikram  R B, Chua  J, Allen  J R, Heaton  D C, Hart  D N, Schousboe  M I. Intranasal amphotericin B reduces the frequency of invasive aspergillosis in neutropenic patients.  Am J Med. 1990;;  90 685-692
• 081 Karthaus  M, Doellmann  T, Klimasch  T, Elser  C, Rosenthal  C, Ganser  A, Heil  G. Intensive intravenous amphotericin B for prophylaxis of systemic fungal infections. Results of a prospective controlled pilot study in acute leukemia patients.  Chemotherapy. 2000;;  46 293-302
• 082 Kauffman  C A, Bradley  S F, Ross  S C, Weber  D R. Hepatosplenic candidiasis: successful treatment with fluconazole.  Am J Med. 1994;;  93 137-141
• 083 Kelsey  S M, Goldman  J M, McCann  S, Newland  A C, Scarffe  J H, Oppenheim  B A, Mufti  G J. Liposomal amphotericin (AmBisome) in the prophylaxis of fungal infections in neutropenic patients: a randomised, double-blind, placebo-controlled study.  Bone Marrow Transplant. 1999;;  23 163-168
• 084 Klingspor  L, Stintzing  G, Fasth  A, Tollemar  J. Deep Candida infection in children receiving allogeneic bone marrow transplants: incidence, risk factors and diagnosis.  Bone Marrow Transplant. 1996;;  17 1043-1049
• 085 Klingspor  L, Stintzing  G, Tollemar  J. Deep Candida infection in children with leukaemia: clinical presentations, diagnosis and outcome.  Acta Paediatr. 1997;;  86 30-36
• 086 Lecciones  J A, Lee  J W, Navarro  E, Witebsky  F G, Marshall  D J, Steinberg  S M et al. Vascular catheter-associated fungemia in cancer patients: analysis of 155 episodes.  Rev Infect Dis. 1992;;  14 875-883
• 087 Lee  J W, Seibel  N L, Amantea  M, Whitcomb  P, Pizzo  P A, Walsh  T J. Safety and pharmacokinetics of fluconazole in children with neoplastic diseases.  J Pediatr. 1992;;  120 987-993
• 088 Leenders  A C, Daenen  S, Jansen  R L, Hop  W C, Lowenberg  B, Wijermans  P W et al. Liposomal amphotericin B compared with amphotericin B deoxycholate in the treatment of documented and suspected neutropenia-associated invasive fungal infections.  Br J Haematol. 1998;;  103 205-212
• 089 Lehrnbecher  T. Haematopoetische Wachstumsfaktoren. Klin Paediatr 2001 (in press):
• 090 Lehrer  R I, Kline  M J. Leukocyte candidacidal activity and resistance to systemic candidiasis in patients with cancer.  Cancer. 1971;;  27 1211-1217
• 091 Lomaestro  B M, Piatek  M A. Update on drug interactions with azole antifungal agents.  Ann Pharmacother. 1998;;  32 915-928
• 092 Lortholary  O, Dupont  B. Antifungal prophylaxis during neutropenia and immunodeficiency.  Clin Microbiol Rev. 1997;;  10 477-504
• 093 MacDonald  L, Baker  C, Chenoweth  C. Risk factors for candidemia in a children's hospital.  Clin Infect Dis. 1998;;  26 642-645
• 094 Maertens  J, Verhaegen  J, Demuynck  H, Brock  P, Verhoef  G, Vandenberghe  P, Van Eldere  J et al. Autopsy-controlled prospective evaluation of serial screening for circulating galactomannan by a sandwich enzyme-linked immunosorbent assay for hematological patients at risk for invasive Aspergillosis.  J Clin Microbiol. 1999;;  37 3223-3228
• 095 Maksymiuk  A W, Thongprasert  S, Hopfer  R, Luna  M, Fainstein  V, Bodey  G P. Systemic candidiasis in cancer patients.  Am J Med. 1984;;  77 20-27
• 096 Marina  N M, Flynn  P M, Rivera  G K, Hughes  W T. Candida tropicalis and Candida albicans fungemia in children with leukemia.  Cancer. 1991;;  68 594-599
• 097 Marr  K A, Seidel  K, Slavin  M A, Bowden  R A, Schoch  H G, Flowers  M E, Corey  L, Boeckh  M. Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized, placebo-controlled trial.  Blood. 2000;;  96 2055-2061
• 098 Marr  K A, Seidel  K, White  T C, Bowden  R A. Candidemia in allogeneic blood and marrow transplant recipients: evolution of risk factors after the adoption of prophylactic fluconazole.  J Infect Dis. 2000;;  181 309-316
• 099 Martino  R, Lopez  R, Sureda  A, Brunet  S, Domingo-Albos  A. Risk of reactivation of a recent invasive fungal infection in patients with hematological malignancies undergoing further intensive chemo-radiotherapy. A single-center experience and review of the literature.  Haematologica. 1997;;  82 297-304
• 100 Mattiuzzi  G N, Blamble  D, Estey  E, Kwari  M, Cortes  J, Giles  F, Kantarijan  H. Ambisome vs. fluconazole plus itraconazole prophylaxis in frintline therapy of acute myelogenous leukemia and myelodysplastic syndrome. In: Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, abstr. 701, page 363. American Society for Microbiology, Washington DC; 2000:
• 101 Menichetti  F, Del Favero  A, Martino  P, Bucaneve  G, Micozzi  A, D'Antonio  D et al. Preventing fungal infection in neutropenic patients with acute leukemia: fluconazole compared with oral amphotericin B. The GIMEMA Infection Program.  Ann Intern Med. 1994;;  120 913-918
• 102 Menichetti  F, Del Favero  A, Martino  P, Bucaneve  G, Micozzi  A, Girmenia  C et al. Itraconazole oral solution as prophylaxis for fungal infections in neutropenic patients with hematologic malignancies: a randomized, placebo-controlled, double-blind, multicenter trial. GIMEMA Infection Program. Gruppo Italiano Malattie Ematologiche dell' Adulto.  Clin Infect Dis. 1999;;  28 250-255
• 103 Meunier  F. Candidiasis.  Eur J Clin Microbiol Infect Dis. 1989;;  8 438-447
• 104 Meunier  F. New methods for delivery of antifungal agents.  Rev Infect Dis. 1989;;  11 Suppl 7 S1605-1612
• 105 Meunier-Carpentier  F, Kiehn  T E, Armstrong  D. Fungemia in the immuno-compromised host. Changing patterns, antigenemia, high mortality.  Am J Med. 1981;;  71 363-370
• 106 Meunier-Carpentier  F, Snoeck  R, Gerain  J, Muller  C, Klastersky  J. Amphotericin B nasal spray as prophylaxis against aspergillosis in patients with neutropenia.  N Engl J Med. 1984;;  311 1056
• 107 Meyers  J D. Fungal infections in bone marrow transplant patients.  Sem Oncol. 1990;;  17 (Suppl 6) S10-13
• 108 Morgenstern  G R, Prentice  A G, Prentice  H G, Ropner  J E, Schey  S A, Warnock  D W. A randomized controlled trial of itraconazole versus fluconazole for the prevention of fungal infections in patients with haematological malignancies. U.K. Multicentre Antifungal Prophylaxis Study Group.  Br J Haematol. 1999;;  105 901-911
• 109 Müller  F M, Groll  A H, Walsh  T J. Current approaches in diagnosis and treatment of fungal infections in HIV-infected children.  Eur J Pediatr. 1999;;  158 187-199
• 110 Müller  F M, Morschhauser  J, Kohler  G, Oelschlaeger  T A, Ziebuhr  W, Hacker  J. Adherence and invasion-two pathogenicity factors in bacterial and fungal pathogens.  Mycoses. 1999;;  42 Suppl 1 39-42
• 111 Müller  F M, Weig  M, Peter  J, Walsh  T J. Azole cross-resistance to ketoconazole, fluconazole, itraconazole and voriconazole in clinical Candida albicans isolates from HIV-infected children with oropharyngeal candidosis.  J Antimicrob Chemother. 2000;;  46 338-340
• 112 Myers  S E, Devine  S M, Topper  R L, Ondrey  M, Chandler  C, O'Toole  K et al. A pilot study of prophylactic aerosolized amphotericin B in patients at risk for prolonged neutropenia.  Leuk Lymphoma. 1992;;  8 229-233
• 113 Nguyen  M H, Peacock  J E Jr, Morris  A J, Tanner  D C, Nguyen  M L, Snydman  D R et al. The changing face of candidemia: emergence of non- Candida albicans species and antifungal resistance.  Am J Med. 1996;;  100 617-623
• 114 Ninane  J. A multicentre study of fluconazole versus oral polyenes in the prevention of fungal infection in children with hematological or oncological malignancies. Multicentre Study Group.  Eur J Clin Microbiol Infect Dis. 1994;;  13 330-337
• 115 Novelli  V, Holzel  H. Safety and tolerability of fluconazole in children.  Antimicrob Agents Chemother. 1999;;  43 1955-1960
• 116 Nucci  M, Biasoli  I, Akiti  T, Silveira  F, Solza  C, Barreiros  G et al. A double-blind, randomized, placebo-controlled trial of itraconazole capsules as antifungal prophylaxis for neutropenic patients.  Clin Infect Dis. 2000;;  30 300-305
• 117 O'Donnell  M R, Schmidt  G M, Tegtmeier  B R, Faucett  C, Fahey  J L, Ito  J et al. Prediction of systemic fungal infection in allogeneic marrow recipients: impact of amphotericin prophylaxis in high-risk patients.  J Clin Oncol. 1994;;  12 827-834
• 118 Offner  F, Cordonnier  C, Ljungman  P, Prentice  H G, Engelhard  D, De Bacquer  D et al. Impact of previous aspergillosis on the outcome of bone marrow transplantation.  Clin Infect Dis. 1998;;  26 1098-1103
• 119 Pagano  L, Antinori  A, Ammassari  A, Mele  L, Nosari  A, Melillo  L et al. Retrospective study of candidemia in patients with hematological malig-nancies. Clinical features, risk factors and outcome of 76 episodes.  Eur J Haematol. 1999;;  63 77-85
• 120 Perfect  J R, Klotman  M E, Gilbert  C C, Crawford  D D, Rosner  G L, Wright  K A, Peters  W P. Prophylactic intravenous amphotericin B in neutropenic autologous bone marrow transplant recipients.  J Infect Dis. 1992;;  140 891-897
• 121 Perfect  J R. Antifungal prophylaxis: to prevent or not.  Am J Med. 1993;;  94 233-234
• 122 Philpott-Howard  J N, Wade  J J, Mufti  G J, Brammer  K W, Ehninger  G. Randomized comparison of oral fluconazole versus oral polyenes for the prevention of fungal infection in patients at risk of neutropenia. Multicentre Study Group.  J Antimicrob Chemother. 1993;;  31 973-984
• 123 Powderly  W G, Mayer  K H, Perfect  J R. Diagnosis and treatment of oropharyngeal candidiasis in patients infected with HIV: a critical reassessment.  AIDS Res Hum Retrovir. 1999;;  15 1405-1412
• 124 Prentice  A G, Bradford  G R. Prophylaxis of fungal infections with itraconazole during remission-induction therapy.  Mycoses. 1989;;  32 Suppl 1 96-102
• 125 Reagan  D R, Pfaller  M A, Hollis  R J, Wenzel  R P. Characterization of the sequence of colonization and nosocomial candidemia using DNA fingerprinting and a DNA probe.  J Clin Microbiol. 1990;;  28 2733-2738
• 126 Rex  J H, Bennett  J E, Sugar  A M, Pappas  P G, van der Horst  C M, Edwards  J E, Washburn  R G et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia.  N Engl J Med. 1994;;  331 1325-1330
• 127 Rex  J H, Pfaller  M A, Galgiani  J N, Bartlett  M S, Espinel-Ingroff  A, Ghannoum  M A et al. Development of interpretive breakpoints for antifungal susceptibility testing: conceptual framework and analysis of in vitro-in vivo correlation data for fluconazole, itraconazole, and Candida infections. Subcommittee on Antifungal Susceptibility Testing of the National Committee for Clinical Laboratory Standards.  Clin Infect Dis. 1997;;  24 235-247
• 128 Reynes  J, Bazin  C, Ajana  F, Datry  A, LeMoing  J P, Chwetzoff  E, Levron  J C. Pharmacokinetics of itraconazole (oral solution) in two groupos of human immunodeficiency virus-infected adults with oral candidiasis.  Antimicrob Agents Chemother. 1997;;  41 2554-2558
• 129 Riley  D K, Pavia  A T, Beatty  P G, Petersen  F B, Spruance  J L, Stokes  R, Evans  T G. The prophylactic use of low-dose amphotericin B in bone marrow transplant patients.  Am J Med. 1994;;  97 509-514
• 130 Ritter  J, Roos  N. Special aspects related to invasive fungal infections in children with cancer. In: Meunier F (ed). Bailleres Clinical Infectious Diseases. London Philadelphia Sydney Tokio Toronto; 1995;: 179-204
• 131 Rodriguez  L J, Rex  J H, Anaissie  E J. Update on invasive candidiasis.  Adv Pharmacol. 1997;;  37 349-400
• 132 Roilides  E, Dignani  M C, Anaissie  E J, Rex  J H. The role of immunoreconstitution in the management of refractory opportunistic fungal infections.  Med Mycol. 1998;;  36 Suppl 1 12-25
• 133 Roth  C, Gebhart  J, Just-Nübling  G, von Eisenhart-Rothe  B, Beinhauer-Reeb  I. Characterization of amphotericin B aerosols for inhalation treatment of pulmonary aspergillosis.  Infection. 1996;;  24 354-360
• 134 Rotstein  C, Bow  E J, Laverdiere  M, Ioannou  S, Carr  D, Moghaddam  N. Randomized placebo-controlled trial of fluconazole prophylaxis for neutropenic cancer patients: benefit based on purpose and intensity of cytotoxic therapy. The Canadian Fluconazole Prophylaxis Study Group.  Clin Infect Dis. 1999;;  28 331-340
• 135 Rousey  S R, Russler  S, Gottlieb  M, Ash  R C. Low-dose amphotericin B prophylaxis against invasive Aspergillus infections in allogeneic marrow transplantation.  Am J Med. 1991;;  91 484-492
• 136 Ruijgrok  E J, Vulto  A G, Van Etten  E W. Aerosol delivery of amphotericin B desoxycholate (Fungizone) and liposomal amphotericin B (AmBisome): aerosol characteristics and in-vivo amphotericin B deposition in rats.  J Pharm Pharmacol. 2000;;  52 619-627
• 137 Saag  M S, Cloud  G A, Graybill  J R, Sobel  J D, Tuazon  C U, Johnson  P C et al. A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. National Institute of Allergy and Infectious Diseases Mycoses Study Group.  Clin Infect Dis. 1999;;  28 291-296
• 138 Saag  M S, Fessel  W J, Kaufman  C A, Merrill  K W, Ward  D J, Moskovitz  B L et al. Treatment of fluconazole-refractory oropharyngeal candidiasis with itraconazole oral solution in HIV-positive patients.  AIDS Res Hum Retroviruses. 1999;;  15 1413-1417
• 139 Saag  M S, Powderly  W G, Cloud  G A, Robinson  P, Grieco  M H, Sharkey  P K et al. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group.  N Engl J Med. 1992;;  326 83-89
• 140 Sallah  S, Semelka  R C, Sallah  W, Vainright  J R, Philips  D L. Amphotericin B lipid complex for the treatment of patients with acute leukemia and hepatosplenic candidiasis.  Leuk Res. 1999;;  23 995-999
• 141 Samonis  G, Rolston  K, Karl  C, Miller  P, Bodey  G P. Prophylaxis of oropharyngeal candidiasis with fluconazole.  Rev Infect Dis. 1990;;  12 Suppl 3 S369-373
• 142 Schaffner  A, Douglas  H, Braude  A. Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to Aspergillus.  J Clin Invest. 1982;;  69 617-631
• 143 Schaffner  A, Schaffner  M. Effect of prophylactic fluconazole on the frequency of fungal infections, amphotericin B use, and health care costs in patients undergoing intensive chemotherapy for hematologic neoplasias.  J Infect Dis. 1995;;  172 1035-1041
• 144 Schmitt  H J, Bernard  E M, Hauser  M, Armstrong  D. Aerosol amphotericin B is effective for prophylaxis and therapy in a rat model of pulmonary aspergillosis.  Antimicrob Agents Chemother. 1988;;  32 1676-1679
• 145 Schmitt  H J, Edwards  F, Andrade  J, Niki  Y, Armstrong  D. Comparison of azoles against aspergilli in vitro and in an experimental model of pulmonary aspergillosis.  Chemotherapy. 1992;;  38 118-126
• 146 Schwartz  S, Behre  G, Heinemann  V, Wandt  H, Schilling  E, Arning  M et al. Aerosolized amphotericin B inhalations as prophylaxis of invasive Aspergillus infections during prolonged neutropenia: results of a prospective randomized multicenter trial.  Blood. 1999;;  93 3654-3661
• 147 Slavin  M A, Osborne  B, Adams  R, Levenstein  M J, Schoch  H G, Feldman  A R et al. Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation - a prospective, randomized, double-blind study.  J Infect Dis. 1995;;  171 1545-1552
• 148 Stein  G E, Mummaw  N. Placebo-controlled trial of itraconazole for treatment of acute vaginal candidiasis.  Antimicrob Agents Chemother. 1993;;  37 89-92
• 149 Stevens  D A, Lee  J Y. Analysis of compassionate use itraconazole therapy for invasive aspergillosis by the NIAID Mycoses Study Group criteria.  Arch Intern Med. 1997;;  157 1857-1862
• 150 Stevens  D A. Itraconazole in cyclodextrin solution.  Pharmacotherapy. 1999;;  19 603-611
• 151 Taylor  T L. Nystatin prophylaxis in immunocompromised children.  Ann Pharmacother. 1996;;  30 534-535
• 152 Timmers  G J, Zweegman  S, Simoons-Smit  A M, van Loenen  A C, Touw  D, Huijgens  P C. Amphotericin B colloidal dispersion (Amphocil) vs fluconazole for the prevention of fungal infections in neutropenic patients: data of a prematurely stopped clinical trial.  Bone Marrow Transplant. 2000;;  25 879-884
• 153 Todeschini  G, Murari  C, Bonesi  R, Pizzolo  G, Amaddi  G, Ambrosetti  A et al. Oral itraconazole plus nasal amphotericin B for prophylaxis of invasive aspergillosis in patients with hematological malignancies.  Eur J Clin Microbiol Infect Dis. 1993;;  12 614-618
• 154 Tollemar  J, Ringden  O, Andersson  S, Sundberg  B, Ljungman  P, Tyden  G. Randomized double-blind study of liposomal amphotericin B (Ambisome) prophylaxis of invasive fungal infections in bone marrow transplant recipients.  Bone Marrow Transplant. 1993;;  12 577-582
• 155 Tricot  G, Joosten  E, Boogaerts  M A, Van de Pitte  J, Cauwenbergh  G. Ketoconazole vs. itraconazole for antifungal prophylaxis in patients with severe granulocytopenia: preliminary results of two nonrandomized studies.  Rev Infect Dis. 1987;;  9 Suppl 1 S94-99
• 156 Trigg  M E, Morgan  D, Burns  T L, Kook  H, Rumelhart  S L, Holida  M D, Giller  R H. Successful program to prevent Aspergillus infections in children undergoing marrow transplantation: use of nasal amphotericin.  Bone Marrow Transplant. 1997;;  19 43-47
• 157 Tsourounis  C, Guglielmo  B J. Aerosolized amphotericin B in prophylaxis of pulmonary aspergillosis.  Ann Pharmacother. 1996;;  30 1175-1176
• 158 US Public Health Services/Infectious Diseases Society of America .Prevention of opportunistic Infections Working Group. 1999 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. Clin Infect Dis 2000; 30: S29-65
• 159 Uzun  O, Anaissie  E J. Antifungal prophylaxis in patients with hematologic malignancies: a reappraisal.  Blood. 1995;;  86 2063-2072
• 160 van Burik  J H, Leisenring  W, Myerson  D, Hackman  R C, Shulman  H M, Sale  G E et al. The effect of prophylactic fluconazole on the clinical spectrum of fungal diseases in bone marrow transplant recipients with special attention to hepatic candidiasis. An autopsy study of 355 patients.  Medicine (Baltimore). 1998;;  77 246-254
• 161 Vartivarian  S, Smith  C B. Pathogenesis, host resistance, and predisposing factors. In: Bodey GP: Candidiasis. Pathogenesis, Diagnosis, and treatment, 2nd ed. Raven Press, New York; 1993;: pp 59-84
• 162 Viscoli  C, Castagnola  E, Giacchino  M, Cesaro  S, Properzi  E, Tucci  F et al. Bloodstream infections in children with cancer: a multicentre surveillance study of the Italian Association of Paediatric Haematology and Oncology.  Eur J Cancer. 1999;;  35 770-774
• 163 Vreugdenhil  G, Van Dijke  B J, Donnelly  J P, Novakova  I R, Raemaekers  J M, Hoogkamp-Korstanje  M A et al. Efficacy of itraconazole in the prevention of fungal infections among neutropenic patients with hematologic malignancies and intensive chemotherapy. A double blind, placebo controlled study.  Leuk Lymphoma. 1993;;  11 353-358
• 164 Wald  A, Leichsenring  W, van Burik  J A, Bowden  R A. Epidemiology of Asper-gillus infections in a large cohort of patients undergoing bone marrow transplantation.  J Infect Dis. 1997;;  175 1459-1466
• 165 Walmsley  S, Devi  S, King  S, Schneider  R, Richardson  S, Ford-Jones  L. Invasive Aspergillus infections in a pediatric hospital: a ten-year review.  Pediatr Infect Dis J. 1993;;  12 673-682
• 166 Walsh  T J, Dixon  D M. Nosocomial aspergillosis: environmental micro-biology, hospital epidemiology, diagnosis and treatment.  Eur J Epidemiol. 1989;;  5 131-142
• 167 Walsh  T J, Groll  A H. Emerging fungal pathogens: evolving challenges to immunocompromised patients for the twenty-first century.  Transpl Infect Dis. 1999;;  1 247-261
• 168 Walsh  T J, Finberg  R W, Arndt  C, Hiemenz  J, Schwartz  C, Bodensteiner  D et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group.  N Engl J Med. 1999;;  340 764-771
• 169 Walsh  T J, Hiemenz  J W, Anaissie  E J. Recent progress and current problems in treatment of invasive fungal infections in neutropenic patients.  Infect Dis Clin North Amer. 1996;;  10 365-400
• 170 Walsh  T J, Lee  J W. Prevention of invasive fungal infections in patients with neoplastic disease.  Clin Infect Dis. 1993;;  17 Suppl 2 S468-480
• 171 Walsh  T J, Roden  M, Roilides  E, Groll  A H. Concepts in design of comparative clinical trials of antifungal therapy in neutropenic patients.  Int J Antimicrob Agents. 2000;;  16 151-156
• 172 Walsh  T J, Viviani  A M, Arathoon  E, Chiou  C, Ghannoum  M A, Groll  A H, Odds  F. New targets and delivery systems for antifungal therapy.  Medical Mycology. 2000;;  38 (Suppl I) 335-347
• 173 Walsh  T J, Whitcomb  P, Piscitelli  S, Figg  W D, Hill  S, Chanock  S J et al. Safety, tolerance, and pharmacokinetics of amphotericin B lipid complex in children with hepatosplenic candidiasis.  Antimicrob Agents Chemother. 1997;;  41 1944-1948
• 174 Walsh  T J, Whitcomb  P O, Revankar  S G, Pizzo  P A. Successful treatment of hepatosplenic candidiasis through repeated cycles of chemotherapy and neutropenia.  Cancer. 1995;;  76 2357-2362
• 175 Weig  M, Müller  F M. Synergism of Voriconazole and Terbinafine against Candida albicans Isolates from Human Immunodeficiency Virus-Infected Patients with Oropharyngeal Candidiasis.  Antimicrob Agents Chemother. 2000;;  45 966-968
• 176 Wey  S B, Mori  M, Pfaller  M A, Woolson  R F, Wenzel  R P. Risk factors for hospital-acquired candidemia. A matched case-control study.  Arch Intern Med. 1989;;  149 2349-2353
• 177 Wingard  J R, Kubilis  P, Lee  L, Yee  G, White  M, Walshe  L et al. Clinical significance of nephrotoxicity in patients treated with amphotericin B for suspected or proven aspergillosis.  Clin Infect Dis. 1999;;  29 1402-1407
• 178 Wingard  J R, Merz  W G, Rinaldi  M G, Johnson  T R, Karp  J E, Saral  R. Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole.  N Engl J Med. 1991;;  325 1274-1277
• 179 Wingard  J R, Merz  W G, Rinaldi  M G, Miller  C B, Karp  J E, Saral  R. Association of Torulopsis glabrata infections with fluconazole prophylaxis in neutropenic bone marrow transplant patients.  Antimicrob Agents Chemother. 1993;;  37 1847-1849
• 180 Wingard  J R. Infections due to resistant Candida species in patients with cancer who are receiving chemotherapy.  Clin Infect Dis. 1994;;  19 Suppl 1 S49-53
• 181 Winston  D J, Chandrasekar  P H, Lazarus  H M, Goodman  J L, Silber  J L, Horowitz  H et al. Fluconazole prophylaxis of fungal infections in patients with acute leukemia. Results of a randomized placebo-controlled, double-blind, multicenter trial.  Ann Intern Med. 1993;;  118 495-503
• 182 Wolff  S N, Fay  J, Stevens  D, Herzig  R H, Pohlman  B, Bolwell  B et al. Fluconazole vs low-dose amphotericin B for the prevention of fungal infections in patients undergoing bone marrow transplantation: a study of the North American Marrow Transplant Group.  Bone Marrow Transplant. 2000;;  25 853-859
• 183 Young  G A, Bosly  A, Gibbs  D L, Durrant  S. A double-blind comparison of fluconazole and nystatin in the prevention of candidiasis in patients with leukaemia. Antifungal Prophylaxis Study Group.  Eur J Cancer. 1999;;  35 1208-1213
• 184 Zhu  L P, Shi  Y Z, Wenig  X H, Müller  F MC. Pulmonary cryptococcosis associated with cryptococcal meningitis in non-AIDS patients: four case reports and a review of the literature. Mycoses 2001 (in press):