New antifungal compounds and strategies for treatment of invasive fungal infections in patients with neoplastic diseases

  • Thomas J. Walsh
  • Caron A. Lyman
Part of the Cancer Treatment and Research book series (CTAR, volume 79)


Patients with neoplastic diseases are predisposed to develop invasive fungal infections as the result of impairments host defense, due principally to pharmacological immunosuppression resulting from intensive cytotoxic chemotherapy, ablative radiation therapy, and corticosteroids. Candida spp., Aspergillus spp., and emerging opportunistic fungal pathogens comprise the principal etiological agents of opportunistic mycoses in neutropenic cancer patients. This chapter will review advances in the development of new antifungal drugs and therapeutic strategies for the treatment of life-threatening mycoses in neutropenic hosts.


Invasive Aspergillosis Antimicrob Agent Invasive Fungal Infection Invasive Candidiasis Neutropenic Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Gold W, Stout HA, Pagona JF, et al. 1955. Amphotericins A & B, antifungal antibiotics produced by a streptomycete. Antibiot Ann, pp 579–586.Google Scholar
  2. 2.
    Kerridge D. 1986. Mode of action of clinically important antifungal drugs. Adv Microb Physiol 27:1–72.PubMedGoogle Scholar
  3. 3.
    Palacios J, Serrano R. 1978. Proton permeability induced by polyene antibiotics. A plausible mechanism for their inhibition of maltose fermentation in yeast. Fede Euro Biochem Soci Lett 91:198–201.Google Scholar
  4. 4.
    Gale EF. 1986. Nature and development of phenotypic resistance to amphotericin B in Candida albicans. Adv Microb Physiol 27:278–320.Google Scholar
  5. 5.
    Medoff G, Kobayashi GS. 1980. Strategies in the treatment of systemic fungal infections. N Engl J Med 302:145–155.PubMedGoogle Scholar
  6. 6.
    Vertut-Croquin A, Bolard J, Chabert M, Gary-Bobo C. 1983. Differences in the interaction of the polyene antibiotic amphotericin B with cholesterol- or ergosterol-containing phospholipid vesicles. A circular dichroism and permeability study. Biochemistry 22:2939–2944.PubMedGoogle Scholar
  7. 7.
    Sokol-Anderson ML, Brajtburg J, Medoff G. 1986. Amphotericin B-induced oxidative damage and killing of Candida albicans. J Infect Dis 154:76–83.PubMedGoogle Scholar
  8. Wilson et al. 191.Google Scholar
  9. 9.
    Brajtburg J, Powderly WG, Kobayashi GS, Medoff G. 1990. Amphotericin B: Current understanding of mechanisms of action. Antimicrob Agents Chemother 34:183–188.PubMedGoogle Scholar
  10. 10.
    Atkinson AJ Jr, Bennett JE. 1978. Amphotericin B pharmacokinetics in humans. Antimicrob Agents Chemother 13:271–276.PubMedGoogle Scholar
  11. 11.
    Benson JM, Nahata MC. 1989. Pharmacokinetics of amphotericin B in children. Antimicrob Agents Chemother 33:1989–1993.PubMedGoogle Scholar
  12. 12.
    Craven PC, Ludden TM, Drutz DJ, Rogers W, Haegek KA, Skradlant HB. 1979. Excretion pathways of amphotericin B. J Infect Dis 140:329–341.PubMedGoogle Scholar
  13. 13.
    Starke JR, Mason O, Kramer WG, Kaplan SL. 1987. Pharmacokinetics of amphotericin B in infants and children. J Infect Dis 155:766–774.PubMedGoogle Scholar
  14. 14.
    Christiansen et al. 1985.Google Scholar
  15. 15.
    Gallis HQ, Drew RH, Pickard WW. 1990. Amphotericin B: 30 years of clinical experience. Revi Infect Dis 12:308–329.Google Scholar
  16. 16.
    Bindschadler DD, Bennett JE. 1969. A pharmacologic guide to the clinical use of amphotericin B. J Infect Dis 120:427–436.PubMedGoogle Scholar
  17. 17.
    Powderly WG, Granich GG, Herzid GP, Krogstad DJ. 1987. HPLC measurement of amphotericin B serum levels in cancer patients. 27th Interscience Conference on Antimicrobial Agents and Chemotherapy, abstract no. 782, Washington, DC.Google Scholar
  18. 18.
    Fields BT Jr, Bates JH, Abernathy RS. 1971. Effect of rapid intravenous infusion on serum concentrations of amphotericin B. Appl Microbiol 22:615–617.PubMedGoogle Scholar
  19. 19.
    Polat, 1979.Google Scholar
  20. 20.
    Utz JP, Garriques IL, Sande MA, Warner JF, Mandell GL, et al. 1975. Therapy of cryptococcosis with a combination of flucytosine and amphotericin B. J Infect Dis 132:368–373.PubMedGoogle Scholar
  21. 21.
    Craven PC, Drutz DJ. 1979. Tissue storage of amphotericin B and amphotericin B methyl ester aspartate. 19th Interscience Conference on Antimicrobial Agents and Chemotherapy, abstract no. 156, Washington, DC.Google Scholar
  22. 22.
    Adamson PC, Rinaldi MG, Pizzo PA, Walsh TJ. 1989. Amphotericin B in treatment of Candida cholecystitis. Pediatr Infect Dis J 8:408–411.PubMedGoogle Scholar
  23. 23.
    Reynolds ES, Tomkiewicz ZM, Dammin GJ. 1963. The renal lesion related to amphotericin B treatment for coccidiodomycosis. Med Clin North Am 47:1149–1154.PubMedGoogle Scholar
  24. 24.
    Daneshmend TK, Warnock DW. 1983. Clinical pharmacokinetics of systemic antifungal drugs. Clin Pharmacokinet 8:17–42.PubMedGoogle Scholar
  25. 25.
    Walsh TJ, Pizzo PA. 1988. Treatment of systemic fungal infections: Recent progress and current problems. Eur J Clin Microbiol Infect Dis 7:460–475.PubMedGoogle Scholar
  26. 26.
    Gelfand JA, Kimball K, Burke JF, et al. 1988. Amphotericin B treatment of human mononuclear cells in vitro results in secretion of tumor necrosis factor and interleukin-1. Clin Res 36:456A.Google Scholar
  27. 27.
    Burks LC, Aisner J, Fortner CL, et al. 1980. Meperidine for the treatment of shaking chills and fever. Arch Intern Med 140:483–484.PubMedGoogle Scholar
  28. 28.
    Koldin MH, Medoff G. 1983. Antifungal chemotherapy. Pediatr Clin North Am 30:49–61.PubMedGoogle Scholar
  29. 29.
    Graybill JR. 1988. Systemic fungal infections: Diagnosis and treatment I. Therapeutic agents. Infect Dis Clin North Am 2:805–825.PubMedGoogle Scholar
  30. 30.
    Maddux MS, Barriere SL. 1980. A review of complications of amphotericin B therapy: Recommendations for prevention and management. Drug Intelli Clin Pharm 14:177–181.Google Scholar
  31. 31.
    Burgess JL, Birchall R. 1972. Nephrotoxicity of amphotericin B, with emphasis on changes in tubular function. Am J Med 53:77–84.PubMedGoogle Scholar
  32. 32.
    Sabra R, Branch RA. 1990. Amphotericin B nephrotoxicity. Drug Saf 5:94–108.PubMedGoogle Scholar
  33. 33.
    Boland et al. 1980.Google Scholar
  34. 34.
    Cheng et al. 1982.Google Scholar
  35. 35.
    Branch RA. 1988. Prevention of amphotericin B-induced renal impairment: A review on the use of sodium supplementation. Arch Intern Med 148:2389–2394.PubMedGoogle Scholar
  36. 36.
    Heidemann HT, Gerkens JF, Spickard WA, Jackson EK, Branch RA. 1983. Amphotericin B nephrotoxicity in humans decreased by salt repletion. Am J Med 75:476–481.PubMedGoogle Scholar
  37. 37.
    Wasan KM, Vadiei K, Lopez-Berestein G, Verani RR, Luke DR. 1990. Pentoxifylline in amphotericin B toxicity rat model. Antimicrob Agents Chemother 34:241–244.PubMedGoogle Scholar
  38. 38.
    Butler WT, Bennett JE, Alling DW, Wertlake PT, Utz JP, Hill GJ III. 1964. Nephrotoxicity of amphotericin B: Early and late effects in 81 patients. Ann Intern Med 61:175–187.PubMedGoogle Scholar
  39. 39.
    Feely J, Heidemann H, Gerkins J, Roberts LJ, Branch RA. 1981. Sodium depletion enhances nephrotoxicity of amphotericin B. Lancet 1:1422–1423.PubMedGoogle Scholar
  40. 40.
    Ohnishi A, Ohnishi T, Stevenhead W, Bobinson RD, Branch RA, et al. 1989. Sodium status influences chronic amphotericin B nephrotoxicity in the rat. Antimicrob Agents Chemother 33:1222– 1227.PubMedGoogle Scholar
  41. 41.
    Branch RA, Jackson EK, Jacqz E, Steen R, Ray WA, et al. 1987. Amphotericin B nephrotoxicity in humans decreased by sodium supplements with coadministration of ticarcillin or intravenous saline. Klin Wochenschrift 65:500–506.Google Scholar
  42. 42.
    Butler WT. 1966. Pharmacology, toxicology and therapeutic usefulness of amphotericin B. JAMA 195:127–131.Google Scholar
  43. 43.
    Warda, J, Barriere SL. 1985. Amphotericin B nephrotoxicity. Drug Intelli Clin Pharma 19:25–26.Google Scholar
  44. 44.
    Barton CH, Pahl M, Vaziri ND, Cesario T. 1984. Renal magnesium wasting associated with amphotericin B therapy. Am J Med 77:471–474.PubMedGoogle Scholar
  45. 45.
    MacGregor RR, Bennett JE, Erslev AJ. 1978. Erythropoietin concentration in amphotericin B-induced anemia. Antimicrob Agents Chemother 14:270–273.PubMedGoogle Scholar
  46. 46.
    Sarosi GA. 1990. Amphotericin B: Still the ‘gold standard’ for antifungal therapy. Postgrad Med 88:151–166.PubMedGoogle Scholar
  47. 47.
    Kennedy MS, Deeg HJ, Siegel M, Crowley JJ, Storb R, Thomas ED. 1983. Acute reaction toxicity with combined use of amphotericin B and cyclosporine A after marrow transplantation. Transplantation 35:211–215.PubMedGoogle Scholar
  48. 48.
    Wright DG, Robichaud KJ, Pizzo PA, Deisseroth AB. 1981. Lethal pulmonary reactions associated with the combined use of amphotericin B and leukocyte transfusions. N Engl J Med 304:1185–1189.PubMedGoogle Scholar
  49. 49.
    Dana BW, Durie BGM, White RF, Huestis DW. 1981. Concomitant administration of granulocyte transfusions and amphotericin B in neutropenic patients: Absence of significant pulmonary toxicity. Blood 57:90–94.PubMedGoogle Scholar
  50. 50.
    Roilides E, Walsh TJ, Rubin M, Venzon D, Pizzo PA. 1990. Effects of antifungal agents on the function of human neutrophils in vitro. Antimicrob Agents Chemother 34:196–201.PubMedGoogle Scholar
  51. 51.
    Burch PA, Karp JE, Merz MG, Kuhlman JE, Fishman EK. 1987. Favorable outcome of invasive aspergillosis in patients with acute leukemia. J Clin Oncol 5:1985–1993.PubMedGoogle Scholar
  52. 52.
    Horn R, Wong B, Kiehn TE, Armstrong D. 1985. Fungemia in a cancer hospital: Changing frequency, earlier onset, and results of therapy. Rev Infect Dis 7:646–655.PubMedGoogle Scholar
  53. 53.
    Walsh TJ. 1990. Invasive pulmonary aspergillosis in patients with neoplastic diseases. Semin Respir Infect 5:111–122.PubMedGoogle Scholar
  54. 54.
    Pannuti CS, Gingrich RD, Pfaller MA, Wenzel RP. 1991. Nosocomial pneumonia in adult patients undergoing bone marrow transplantation: A 9-year study. J Clin Oncol 9:77–84.PubMedGoogle Scholar
  55. 55.
    Pizzo PA, Robichaud KJ, Gill FA, Witebsky FG. 1982. Empirical antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. Am J Med 72:101–111.PubMedGoogle Scholar
  56. 56.
    EORTC International Antimicrobial Therapy Cooperative Group. 1989. Empiric antifungal therapy in febrile granulocytopenic patients. Am J Med 86:668–672.Google Scholar
  57. 57.
    Ahrens J, Graybill JR, Craven PC, Taylor RL. 1984. Treatment of experimental murine candidiasis with liposome-associated amphotericin B. Sabouraudia 22:163–166.PubMedGoogle Scholar
  58. 58.
    Juliano RL, Lopez Berestein G, Hopfer R, Mehta R, Mehta K, Mills K. 1985. Selective toxicity and enhanced therapeutic index of liposomal polyene antibiotics in systemic fungal infections. Ann NY Acad Sci 446:390–402.PubMedGoogle Scholar
  59. 59.
    Sculier JP, Coune A, Meunier F, Brassine C, Laduron C, Hollaert C, Collette N, Heymans C, Klastersky J. 1988. Pilot study of amphotericin B entrapped in sonicated liposomes in cancer patients with fungal infections. Eur J Cancer Clin Oncol 24:527–538.PubMedGoogle Scholar
  60. 60.
    Szoka FC Jr, Milholland D, Barza M. 1987. Effect of lipid composition and liposome size on toxicity and in vitro fungicidal activity of liposome-intercalated amphotericin B. Antimicrob Agents Chemother 31:421–429.PubMedGoogle Scholar
  61. 61.
    Mehta T, Lopez-Bernstein G, Hopfer R, Mills K, Juliano RL. 1984. Liposomal amphotericin B is toxic to fungal cells but not to mammalian cells. Biochem Biophys Acta 770:230–234.PubMedGoogle Scholar
  62. 62.
    Lopez-Berestein G, Fainstein V, Hopfer R, Mehta K, Sullivan MP, Keating M, Rosenblum MG, Mehta RT, Luna M, Hersh EM, Reuben J, Juliano RL, Bodey GP. 1985. Liposomal amphotericin B for the treatment of systemic fungal infections in patients with cancer: A preliminary study. J Infect Dis 151:704–710.PubMedGoogle Scholar
  63. 63.
    Clark JM, Whitney RR, Olsen SJ, George RJ, Swerdel MR, Kunselman L, Bonner DP. 1991. Amphotericin B lipid complex therapy of experimental fungal infections in mice. Antimicrob Agents Chemother 35:615–621.PubMedGoogle Scholar
  64. 64.
    Adler-Moore J, Proffitt RT. 1993. Development, characterization, efficacy, and mode of action of AmBisome, a unilamellar liposomal formulation of amphotericin B. J Liposomal Res 3:429–450.Google Scholar
  65. 65.
    Guo LSS, Fielding RM, Mufson D. 1990. Pharmacokinetic study of a novel amphotericin B colloidal dispersion with improved therapeutic index. Ann NY Acad Sci 618:586–588.Google Scholar
  66. 66.
    Lopez-Berestein et al. 1984.Google Scholar
  67. 67.
    Gondal et al. 1989.Google Scholar
  68. 68.
    Proffitt et al. 1991.Google Scholar
  69. 69.
    Lee JW, Amantea M, Navarro E, Francis P, McManus E, Schaufele R, Bacher J, Pizzo PA, Walsh TJ. 1994. Pharmacokinetics and safety of a unilamellar formulation of liposomal amphotericin B (AmBisome) in rabbits. Antimicrob Agents Chemother 38:713–718.PubMedGoogle Scholar
  70. 70.
    Sounders et al. 1991.Google Scholar
  71. 71.
    Fielding RM, Smith PC, Wang LH, Porter J, Guo LSS. 1991. Comparative pharmacokinetics of amphotericin B after administration of a novel colloidal delivery system, ABCD, and a conventional formulation to rats. Antimicrob Agents Chemother 35:1208–1213.PubMedGoogle Scholar
  72. 72.
    Barwicz et al. 1991.Google Scholar
  73. 73.
    Francis P, Lee JW, Hoffman A, Peter J, Francesconi A, Bacher J, Shelhamer J, Pizzo PA, Walsh TJ. 1994. Efficacy of unilamellar liposomal amphotericin B in treatment of pulmonary aspergillosis in persistently granulocytopenic rabbits: The potential role of bronchoalveolar lavage D-mannitol and galactomannan as markers of infection. J Infect Dis 169:356–368.PubMedGoogle Scholar
  74. 74.
    Patterson TF, Miniter P, Dijkstra J, Szoka FC, Jr, Ryan JL, Andriole VT. 1989. Treatment of experimental invasive aspergillosis with novel amphotericin B/cholesterol-sulfate complexes. J Infect Dis 159:717–724.PubMedGoogle Scholar
  75. 75.
    Allende et al. 1994Google Scholar
  76. 76.
    Meunier F. 1989. New methods for delivery of antifungal agents. Rev Infect Dis 11 (Suppl 7):s1605–s1612.PubMedGoogle Scholar
  77. 77.
    Levine SJ, Walsh TJ, Martinez A, Eichacker PQ, Lopez-Berestein G, Natanson C. 1991. Hypoxemia, pulmonary hypertension, and depression of cardiac output as sequelae of liposomal amphotericin B infusion. Ann Intern Med 114:664–666.PubMedGoogle Scholar
  78. 78.
    Lopez-Berestein G. 1986. Liposomal amphotericin B in the treatment of fungal infections. Ann Intern Med 105:130–131.PubMedGoogle Scholar
  79. 79.
    Walsh TJ, Hiemenz JW, Seibel N, Anaissie EJ. 1994. Amphotericin B lipid complex in the treatment of 228 cases of invasive mycosis. Abstracts of the 34th Interscience Conference on Antimicrobial Agents in Chemotherapy abstract M69, p 247.Google Scholar
  80. 80.
    Ringden O, Meunier F, Tollemar J, Ricci P, Tura S, Kuse E, Viviani MA, Gorin NC, Klastersky J, Fenaux P, Prentice HG, Ksionski G. 1991. Efficacy of amphotericin B encapsulated in liposomes (AmBisome) in the treatment of invasive fungal infections in immunocompromised patients. J Antimicrob Chemother 28(Suppl B):63–72.Google Scholar
  81. 81.
    Tollemar J, Ringden O, Andersson S, et al. 1993. Prophylactic use of liposomal amphotericin B (AmBisome) against fungal infections: A randomized trial in bone marrow transplant recipients. Transplant Proc 25:1495–1497.PubMedGoogle Scholar
  82. 82.
    Mehta RT, Hopfer RL, Gunner LA, Juliano RL, Lopez-Berestein G. 1987. Formulation, toxicity, and antifungal activity in vitro of liposome-encapsulated nystatin as therapeutic agent for systemic candidiasis. Antimicrob Agents Chemother 31:1897–1900.PubMedGoogle Scholar
  83. 83.
    Mehta RT, Hopfer RL, McQueen T, Juliano RL, Lopez-Berestein G. 1987. Toxicity and therapeutic effects in mice of liposome-encapsulated nystatin for systemic fungal infections. Antimicrob Agents Chemother 31:1901–1903.PubMedGoogle Scholar
  84. 84.
    Duschinsky R, Pleven E, Heidelberger C. 1957. The synthesis of 5–fluoropyrimidines. J Am Chem Soc 79:4559–4560.Google Scholar
  85. 85.
    Berger J, Duschinsky R. 1962. Control of fungi with 5-fluorocytosine. United States Patent Application Service No. 181, p 822.Google Scholar
  86. 86.
    Grunberg E, Titsworth E, Bennett M. 1964. Chemotherapeutic activity of 5-fluorocytosine. Antimicrob Agents Chemother 3:566–568.Google Scholar
  87. 87.
    Medoff et al. 1972.Google Scholar
  88. 88.
    Francis P, Walsh TJ. 1992. The evolving role of flucytosine in immunocompromised patients: New insights into safety, pharmacokinetics, and antifungal therapy. Rev Infect Dis 15:1003–1018.Google Scholar
  89. 89.
    Polak A, Scholer HJ. 1973. Fungistatic activity, uptake and incorporation of 5-fluorocytosine in Candida albicans, as influenced by pyrimidines and purines. II. Studies on distribution and incorporation. Pathol Microbiol 39:334–347.Google Scholar
  90. 90.
    Diasio RB, Bennett JE, Myers CE. 1978. Mode of action of 5–fluorocytosine. Biochemi Pharmacol 27:703.Google Scholar
  91. 91.
    Polak A, Grenson M. 1973. Evidence for a common transport system for cytosine, adenine and hypoxanthine in Saccharomyces cerevisiae and Candida albicans. Eur J Biochem 32:276–282.PubMedGoogle Scholar
  92. 92.
    Armstrong D, Schmitt HJ. Older Drugs. 1990. In: Ryley JF, ed Chemotherapy of Fungal Diseases. Berlin: Springer-Verlag, pp 439–454.Google Scholar
  93. 93.
    Cutler RE, Blair AD, Kelly MR. 1978. Flucytosine kinetics in subjects with normal and impaired renal function. Clin Pharmacol Ther 24:333–342.PubMedGoogle Scholar
  94. 94.
    Schonebeck J, Polak A, Fernex M. 1973. Pharmacokinetic studies on the oral antimycotic agent 5-fluorocytosine in individuals with normal and impaired kidney function. Chemotherapy 18:321– 326.PubMedGoogle Scholar
  95. 95.
    Block ER, Bennett JE, Livoti LG, Klein WJ, MacGregor RR, Henderson L. 1974. Flucytosine and amphotericin B: Hemodialysis effects on the plasma concentration and clearance. Ann Intern Med 80:613–617.PubMedGoogle Scholar
  96. 96.
    Hoeprich 1989.Google Scholar
  97. 97.
    Bennett JE. 1977. Flucytosine. Ann Intern Med 86:319–322.Google Scholar
  98. 98.
    Kauffman CA, Frame PT. 1977. Bone marrow toxicity associated with 5-fluorocytosine therapy. Antimicrob Agents Chemother 11:244–247.PubMedGoogle Scholar
  99. 99.
    Diasio RB, Lakings DE, Bennett JE. 1978. Evidence for conversion of 5-fluorocytosine to 5-fluorouracil in humans. Possible factor in 5-fluorocytosine clinical toxicity. Antimicrob Agents Chemother 14:903–908.PubMedGoogle Scholar
  100. 100.
    Harris BE, Manning BW, Federle TW. 1986. Conversion of 5-fluorocytosine to 5-fluorouracil by human intestinal microflora. Antimicrob Agents Chemother 29:44–48.PubMedGoogle Scholar
  101. 101.
    Montgomerie JZ, Edwards JE, Guze LB. 1975. Synergism of amphotericin B and 5-fluorocytosine for Candida species. J Infect Dis 132:82–86.PubMedGoogle Scholar
  102. 102.
    Smego RA, Perfect JR, Durack DT. 1984. Combined therapy with amphotericin B and flucytosine for Candida meningitis. Rev Infect Dis 6:791–801.PubMedGoogle Scholar
  103. 103.
    Thaler M, Bacher J, O’Leary T, Pizzo PA. 1988. An experimental model of candidiasis in rabbits with prolonged neutropenia: Its evaluation of single drug and combination antifungal therapy. J Infect Dis 158:80–88.PubMedGoogle Scholar
  104. 104.
    Bennett JE, Dismukes WE, Haywood M, Duma RJ, Medoff G, Sande MA, Gallis H, Leonard J, Fields BT, Bradshaw M, Haywood H, McFee ZA, Cate TR, Cobbs CG, Warner JF, Alling DW. 1979. A comparison of amphotericin B alone and in combination with flucytosine in the treatment of cryptococcal meningitis. N Engl J Med 301:126–131.PubMedGoogle Scholar
  105. 105.
    Fujita NK, Reynard M, Sapico FL, Guzel B, Edwards JE. 1981. Cryptococcal intracerebral mass lesions: The role of computer tomography and non-surgical management. Ann Intern Med 94:382–388.PubMedGoogle Scholar
  106. 106.
    Larsen RA, Leal MA, Chan LS. 1990. Fluconazole compared with amphotericin plus flucytosine for cryptococcal meningitis in AIDS. Ann Intern Med 113:183–187.PubMedGoogle Scholar
  107. 107.
    Woolley DW. 1944. Some biological effects produced by benzimidazole and their reversal by purines. J Biol Chem 152:225–232.Google Scholar
  108. 108.
    van den Bossche H. 1985. Biochemical targets for antifungal azole derivatives: Hypothesis on the mode of action. In: McGinnis M, ed Current Topics in Medical Mycology. New York: Springer-Verlag, pp 313–351.Google Scholar
  109. 109.
    van den Bossche H, Willemsens G, Cools W, Marichal P, Lauwers W. 1983. Hypothesis on the molecular basis of the antifungal activation of N-substituted imidazoles and triazoles. Biochem Soc Transact 11:665–667.Google Scholar
  110. 110.
    DeNollin S, Van Belle H, Goossens F, Thone F, Borgers M. 1977. Cytochemical and biochemical studis of yeasts after in vitro exposure to miconazole. Antimicrob Agents Chemother 11:500–513.Google Scholar
  111. 111.
    Uno J, Shigematsu ML, Arai T. 1982. Primary site of action of ketoconazole on Candida albicans. Antimicrob Agents Chemother 21:912–918.PubMedGoogle Scholar
  112. 112.
    Buchel KH, Draber W, Regel E, Plempel M. 1972. Synthesis and properties of clotrimazole and other antimycotic 1-triphenyl-methyl imidazoles. Drugs Made in Germany 15:79–94.Google Scholar
  113. 113.
    Godefroi EF, Heeres J, VanCutsem J, Janssen PAJ. 1969. The preparation and antimycotic properties of derivatives of 1-phenethylimidazole. J Med Chem 12:784–791.PubMedGoogle Scholar
  114. 114.
    Holt RJ, Neumann RL. 1972. Laboratory assessment of the antimycotic drug clotrimazole. J Clin Pathol 25:1089–1097.PubMedGoogle Scholar
  115. 115.
    Heel RC, Brogden RN, Parkes GE, Speight TM, Avery GS. 1980. Miconazole: A preliminary review of its therapeutic efficacy in systemic fungal infections. Drugs 19:7–30.PubMedGoogle Scholar
  116. 116.
    Fainstein V, Bodey GP. 1980. Cardiorespiratory toxicity due to miconazole. Ann Intern Med 93:432–433.PubMedGoogle Scholar
  117. 117.
    Wingard JR, Vaughn WP, Braine HG, Merz WG, Sarai R. 1987. Prevention of fungal sepsis in patients with prolonged neutropenia: A randomized, double-blind, placebo-controlled trial of intravenous miconazole. Am J Med 83:1103–1110.PubMedGoogle Scholar
  118. 118.
    Galgiani JN, Stevens DA, Graybill JR, Stevens DL, Tillinghast AJ, Levine HB. 1984. Pseu-dallescheria boydii infections treated with ketoconazole: Clinical evaluations of seven patients and in vitro susceptibility tests. Chest. 86:219–224.PubMedGoogle Scholar
  119. 119.
    Van Cutsem J. 1983. The antifungal activity of ketoconazole. Am J Med 74(Suppl 1B):9–15.PubMedGoogle Scholar
  120. 120.
    Daneshmend TK, Warnock DW. 1988. Clinical pharmacokinetics of ketoconazole. Clin Pharmacokinet 14:13–34.PubMedGoogle Scholar
  121. 121.
    Heel RC, Brgden RN, Carmine A, Morley PA, Speight TM, Avery GS. 1982. Ketoconazole: A review of its therapeutic efficacy in superficial and systemic fungal infections. Drugs 23:1–36.PubMedGoogle Scholar
  122. 122.
    Shadomy S, Espinel-Ingroff A, Tartaglione TA, Dismukes WE, NIAID Mycoses Study Group. 1986. Treatment of systemic mycosis with ketoconazole: Studies of ketoconazole serum levels. Mykosen 29:195–209.PubMedGoogle Scholar
  123. 123.
    Lelawongs P, Barone JA, Colaizzi JL, Hsuan ATM, Mechlinski W, LeGendre R, Guarnieri J. 1988. Effect of food and gastric acidity on absorption of orally administered ketoconazole. Clin Pharm 7:228–235.PubMedGoogle Scholar
  124. 124.
    Lake-Bakaar G, Tom W. Lake-Bakaar D, Gupta N, Beidas S, Elsakr M, Straus E. 1988. Gastropathy and ketoconazole malabsorption in the acquired immunodeficiency syndrome. Ann Intern Med 109:471–473.PubMedGoogle Scholar
  125. 125.
    Graybill JR. 1989. New antifungal agents. Eur J Clin Microbiol Infect Dis 8:402–412.PubMedGoogle Scholar
  126. 126.
    Johnson RJ, Blair AD, Ahmad S. 1985. Ketoconazole kinetics in chronic peritoneal dialysis. Clin Pharmacol Therap 37:325–329.Google Scholar
  127. 127.
    Dismukes WE, Stamm AM, Graybill JR, Craven PC, Stevens DA, Stiller RL, Sarosi GA, Medoff G, Gregg CR, Gallis HA, Fields Jr, BT, Marier RL, Kerkering TM, Kaplowitz LG, Cloud G, Bowles C, Shadomy S. 1983. Treatment of systemic mycoses with ketoconazole: Emphasis on toxicity and clinical responsiveness. Ann Intern Med 98:13–20.PubMedGoogle Scholar
  128. 128.
    Sugar AM, Alsip S, Galgiani JN, Graybill JR, Dismukes WE, Cloud GA, Craven PC, Stevens DA. 1987. Pharmacology and toxicity of high-dose ketoconazole. Antimicrob Agents Chemother 31:1874–1878.PubMedGoogle Scholar
  129. 129.
    Pont A, Graybill JR, Craven PC, Galgiani JN, Dismukes WE, Reitz RE, Stevens DA, the NIAID Mycoses Study Group. 1984. High-dose ketoconazole and adrenal and testicular function in man. Arch Intern Med 144:2150.PubMedGoogle Scholar
  130. 130.
    Loose DS, Kan PB, Hirst MA, Marcus RA, Feldman D. 1983. Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes. J Clin Invest 71:495–499.Google Scholar
  131. 131.
    Pont A, Williams PL, Loose DS, Feldman D, Reitz RE, Bochra C, Stevens DA. 1982. Ketoconazole blocks adrenal steroid synthesis. Ann Intern Med 97:370–372.PubMedGoogle Scholar
  132. 132.
    Lewis JH, Zimmerman HJ, Benson GD, Ishak KG. 1984. Hepatic injury associated with ketoconazole therapy: Analysis of 33 cases. Gastroenterology 86:503–513.PubMedGoogle Scholar
  133. 133.
    Shepard JH, Simmons RL. 1986. Cyclosporin-ketoconazole: A potentially dangerous drug interaction. Clin Pharmacol 6:468.Google Scholar
  134. 134.
    Engelhard D, Stutman HR, Marks MI. 1984. Interaction of ketoconazole with rifampin and isoniazid. N Eng J Med 311:1681–1683.Google Scholar
  135. 135.
    Daneshmend TK, Warnock DW, Ene MD, Johnson EM, Potten MR, Richardson MD, Williamson PJ. 1984. Influence of food on the pharmacokinetics of ketoconazole. Antimicrob Agents Chemother 25:1–3.PubMedGoogle Scholar
  136. 136.
    Walsh TJ, Rubin M, Hathorn J, Gress J, Thaler M, et al. 1991. Amphotericin B as. high-dose ketoconazole for empirical antifungal therapy among febrile, granulocytopenic cancer patients. Arch Intern Med 151:765–770.PubMedGoogle Scholar
  137. 137.
    Ringel SM. 1990. New antifungal agents for the systemic mycoses. Mycopathologia 109:75–87.PubMedGoogle Scholar
  138. 138.
    Bennett JE. 1990. Antifungal agents. In: Mandell et al., eds Principles and Practice of Infectious Diseases, 3rd ed, pp 361–370, New York: Churchill Livingston.Google Scholar
  139. 139.
    Grant SM, Clissold SP. 1989. Itraconazole: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in superficial and systemic mycoses. Drugs 37:310–344.PubMedGoogle Scholar
  140. 140.
    Richardson K, Cooper K, Marriott MS, Tarbit MH, Troke PF, Whittle PJ. 1990. Discovery of fluconazole, a novel antifungal agent. Rev Infect Dis 12(Suppl 3):S267–S271.PubMedGoogle Scholar
  141. 141.
    Warnock DW. 1989. Itraconazole and fluconazole: New drugs for deep fungal infection. J Antimicrob Chemother 24:275–280.PubMedGoogle Scholar
  142. 142.
    Hardin TC, Graybill JR, Fetchick R, Woestenborghs R, Rinaldi MG, et al. 1988. Pharmacokinetics of itraconazole following oral administration to normal volunteers. Antimicrob Agents Chemother 32:1310–1313.PubMedGoogle Scholar
  143. 143.
    Tricot G, Joosten E, Boogaerts MA, Van de Pitte J, Cauwenbergh G. 1987. Ketoconazole vs. itraconazole for antifungal prophylaxis in patients with severe granulocytopenia: Preliminary results of two nonrandomized studies. Rev Infect Dis 9(Suppl l):94–99.Google Scholar
  144. 144.
    Wishart JM. 1987. The influence of food on the pharmacokinetics of itraconazole in patients with superficial fungal infection. Am Acad Dermatol 220–223.Google Scholar
  145. 145.
    Heykants J, Michiels M, Meuldermans W, Monbaliu J, Lavrijsen K, Van Peer A, Levron JC, Woestenborghs R, Cauwenbergh G. 1987. The pharmacokinetics of itraconazole in animals and man: An overview. In: Fromtling RA, ed Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents. Barcelona: JR Prous Science, pp 223–249.Google Scholar
  146. 146.
    Van Cutsem J, Van Gerven F, Janssen PAJ. 1987. Activity of orally, topically, and parenterally administered itraconazole in the treatment of superficial and deep mycoses: Animal models. Rev Infect Dis 9:S15–S32.PubMedGoogle Scholar
  147. 147.
    Boelaert J, Schurgers M, Matthys E, Daneels R, Van Peer A, et al. 1988. Itraconazole pharmacokinetics in patients with renal dysfunction. Antimicrob Agents Chemother 32:1595–1597.PubMedGoogle Scholar
  148. 148.
    Novakova I, Donnelly P, De Witte T, DePauw B, Boezeman J, et al. 1987. Itraconazole and cyclosporin nephrotoxicity. Lancet 2:920–921.PubMedGoogle Scholar
  149. 149.
    Trenk D, Brett W, Jahnchen E, Birnbaum D. 1987. Time course of cyclosporine/itraconazole interaction. Lancet 2:1335–1336.PubMedGoogle Scholar
  150. 150.
    Berenguer J, Ali N, Allende MC, Lee JW, Garrett K, Battaglia S, Rinaldi MG, Pizzo PA, Walsh TJ. 1994. Itraconazole in experimental pulmonary aspergillosis: Comparison with amphotericin B, interaction with cyclosporin A, and correlation between therapeutic response and itraconazole plasma concentrations. Antimicrob Agents Chemother 38:1303–1308.PubMedGoogle Scholar
  151. 151.
    Hay RJ, Clayton YM, Moore MK, Midgely G. 1988. An evaluation of itraconazole in the management of onychomycosis. Br J Dermatol 119:359–366.PubMedGoogle Scholar
  152. 152.
    Graybill JR. 1990. Systemic azole antifungal drugs—into the 1990s. In: Ryley JF, ed Chemotherapy of Fungal Diseases. Berlin: Springer-Verlag, pp 453–482.Google Scholar
  153. 153.
    Cauwenbergh G, DeDoncker P, Stoops K, DeDier AM, Goyvaerts H, Schuermans V. 1987. Itraconazole in the treatment of human mycoses: Review of three years of clinical experience. Rev Infect Dis 9(Suppl 1):S146–S152.PubMedGoogle Scholar
  154. 154.
    Sharkey PK, Rinaldi MG, Lerner C, Fetchick R, Dunn JF, Graybill JR. 1988. High dose itraconazole in the treatment of severe mycoses. 28th Interscience Conference of Antimicrobial Agents and Chemotherapy, abstract 575, Los Angeles.Google Scholar
  155. 155.
    Dupont B, Drouhet, E. 1988. The treatment of aspergillosis with azole derivatives. In: Van den Bossche H, Mackenzie DWR, Cauwenbergh G, eds Aspergillus and Aspergillosis. New York: Plenum, pp 243–251.Google Scholar
  156. 156.
    Denning DW, Tucker RM, Hanson LH, Stevens DA. 1989. Treatment of invasive aspergillosis with itraconazole. Am J Med 86:791–800.PubMedGoogle Scholar
  157. 157.
    Viviani MA, Tortorano AM, Pagano A, et al. 1990. European experience with itraconazole in systemic mycoses. J Am Acad Dermatol 23:587–593.PubMedGoogle Scholar
  158. 158.
    Denning DW, Stevens DA. 1991. Efficacy of cilofungin alone and in combination with amphotericin B in a murine model of disseminated aspergillosis. Antimicrob Agents Chemother 35:1329–1333.PubMedGoogle Scholar
  159. 159.
    Vreugdenhil G, Van Dijke BJ, Donnelly JP, Novakova IRO, Raemaekers JMM, Hoogkamp-Korstanje MAA, De Pauw BE. 1993. Efficacy of itraconazole in the prevention of fungal infections among neutropenic patients with hematological malignancies and intensive chemotherapy. A double blind, placebo controlled study. Leuk Lymphoma 11:353–358.PubMedGoogle Scholar
  160. 160.
    Boogaerts MA, Verhoef GE, Zachee P, Demuynck H, Verbist L, DeBeule K. 1989. Antifungal prophylaxis with itraconazole in prolonged neutropenia: Correlation with plasma levels. Mycoses 32(Suppl 1): 103–108.PubMedGoogle Scholar
  161. 161.
    Ganer A, Arathoon E, Stevens DA. 1987. Initial experience in therapy for progressive mycoses with itraconazole, the first clinically studied triazole. Rev Infect Dis 9:S77–S86.PubMedGoogle Scholar
  162. 162.
    Sharkey K, Graybill JR, Rinaldi MG, et al. 1990. Itraconazole treatment of phaeohyphomycosis. J Am Acad Dermatol 23:577–586.PubMedGoogle Scholar
  163. 163.
    Negroni R, Palmierei O, Koren F, Tiraboschi IN, Galimberti RL. 1987. Oral treatment of paracoccidioidomycosis and histoplasmosis with itraconazole in humans. Rev Infect Dis 9:S47–S50.PubMedGoogle Scholar
  164. 164.
    Philips P, Fetchick R, Weisman I, Foshee S, Graybill JR. 1987. Tolerance to and efficacy of itraconazole in treatment of systemic mycoses: Preliminary results. Rev Infect Dis 9:S87–S93.Google Scholar
  165. 165.
    Wheat LJ, Hafner RE, Wulfsohn M, Johnson J, Owens S. 1991. Itraconazole is effective maintenance treatment for prevention of relapse of histoplasmosis in AIDS: Prospective multicenter non-comparative trial.Google Scholar
  166. 166.
    Shaw JTB, Tarbit MH, Troke PF. 1987. Cytochrome P-450 mediated sterol synthesis and metabolism: Differences in sensitivity to fluconazole and other azoles. In: Fromtling RA, eds Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents. Barcelona: JR Prous, pp 125–139.Google Scholar
  167. 167.
    Galgiani JN. 1987. Antifungal susceptibility tests. Antimicrob Agents Chemother 31:1867–1870.PubMedGoogle Scholar
  168. 168.
    National Committee for Clinical Laboratory Standards. 1992. Reference method for broth dilution antifungal susceptibility testing of yeasts. Proposed Standard. NCCLS document M27–P. Villanova, PA: NCCLS.Google Scholar
  169. 169.
    Pfaller MA, Dupont B, Kobayashi GS, Muller J, Rinaldi MG, Shadomy S, Troke PF, Walsh TJ, Warnock DW. 1992. Standardized susceptibility testing of fluconazole: An international collaborative study. Antimicrob Agents Chemother 36:1805–1809.PubMedGoogle Scholar
  170. 170.
    Humphrey MJ, Jevons S, Tarbit MH. 1985. Pharmacokinetic evaluation of UK-49, 858, a metabolically stable triazole antifungal drug, in animals and humans. Antimicrob Agents Chemother 28:648–653.PubMedGoogle Scholar
  171. 171.
    Brammer KW, Farrow PR, Faulkner JK. 1990. Pharmacokinetics and tissue penetration of fluconazole in humans. Rev Infect Dis 12(Suppl 3):S318–S326.PubMedGoogle Scholar
  172. 172.
    Drew RH, Perfect JR, Gallis HE. 1988. Use of fluconazole in a patient with documented malabsorption of ketoconazole. Clin Pharm 7:622–623.PubMedGoogle Scholar
  173. 173.
    Foulds G, Wajszczuk C, Weidler DJ, Garg DC, Gibson P. 1987. Steady state parenteral kinetics of fluconazole in man. 1st International Conference on Drug Research and Immunologic Infectious Diseases, abstract P-6.Google Scholar
  174. 174.
    Shiba K, Saito A, Miyahara T. 1989. Pharmacokinetic evaluation of fluconazole in healthy volunteers. Jpn J Antibiot 42:17–30.PubMedGoogle Scholar
  175. 175.
    Brammer KW, Tarbit MH. 1987. A review of the pharmacokinetics of fluconazole (UK-49, 858) in laboratory animals and man. In: Fromtling RA, ed Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents. Barcelona: JR Prous Science, pp 141–149.Google Scholar
  176. 176.
    Lee JW, Seibel NI, Amantea MA, Whitcomb P, Pizzo PA, Walsh TJ. 1992. Safety, tolerance, and pharmacokinetics of fluconazole in children with neoplastic diseases J Pediatr 120:987–993.PubMedGoogle Scholar
  177. 177.
    Ebden P, Neill P, Farrow PR. 1989. Sputum levels of fluconazole in humans. Antimicrob Agents Chemother 33:963–964.PubMedGoogle Scholar
  178. 178.
    Savani DV, Perfect JR, Cobo LM, Durack DT. 1987. Penetration of new azole compounds into the eye and efficacy in experimental Candida endophthalmitis. Antimicrob Agents Chemother 31:6–10.PubMedGoogle Scholar
  179. 179.
    Walsh, TJ, Foulds G, Pizzo PA. 1989. Pharmacokinetics and tissue penetration of fluconazole in rabbits. Antimicrobial Agents Chemother 33:467–469.Google Scholar
  180. 180.
    Perfect JR, Durack DT. 1985. Penetration of imidazoles and triazoles into cerebrospinal fluid in rabbits. J Antimicrob Chemother 16:81–86.PubMedGoogle Scholar
  181. 181.
    Arndt CAS, Walsh TJ, McCully CL, Balis FM, Pizzo PA, Poplack DG. 1988. Fluconazole penetration into cerebrospinal fluid: Implications for treating fungal infections of the central nervous system. J Infect Dis 157:178–180.PubMedGoogle Scholar
  182. 182.
    Foulds G, Brennan DR, Wajszczuk C, Catanzaro A, Carg DC, Knopf W, Rinaldi M, Weidler DJ. 1988, Fluconazole penetration into cerebrospinal fluid in humans. J Clin Pharmacol 28:363–366.PubMedGoogle Scholar
  183. 183.
    Tucker RM, Williams PL, Arathoon EG, Levine BE, Hartstein AI, Hanson LH, Stevens DA. 1988. Pharmacokinetics of fluconazole in cerbrospinal fluid and serum in human coccidioidal meningitis. Antimicrob Agents Chemother 32:369–373.PubMedGoogle Scholar
  184. 184.
    Grant SM, Clissold SP. 1990. Fluconazole: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses. Drugs 39:877–916.PubMedGoogle Scholar
  185. 185.
    Saag MS, Dismukes WE. 1988. Azole antifungal agents: Emphasis on new triazoles. Antimicrob Agents Chemother 32:1–8.PubMedGoogle Scholar
  186. 186.
    Tachibana M, Noguchi Y, Monro AM. 1987. Toxicology of fluconazole in experimental animals. In: Fromtling RA, ed Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents. Barcelona: JR Prous, pp 93–102.Google Scholar
  187. 187.
    Mitchell AS, Holland JT. 1989. Fluconazole and phenytoin: A predictable interaction. Bri Med J 298:1315.Google Scholar
  188. 188.
    Lazar JD, Wilner KD. 1990. Drug interactions with fluconazole. Rev Infect Dis 12(Suppl 3):S327–S333.PubMedGoogle Scholar
  189. 189.
    Walsh, TJ, Lee J, Aoki S, Mechinaud F, Bacher J, Lecciones J, Thomas V, Rubin M, Pizzo PA. 1990. Experimental basis for use of fluconazole for preventive or early treatment of disseminated candidiasis in granulocytopenic hosts. Rev Infect Dis 12(Suppl 3):S307–S317.PubMedGoogle Scholar
  190. 190.
    Goodman J, Buell D, Gilbert G, for the Seventeen Member Marrow Transplant Study Group. 1991. Fluconazole prevents fungal infections in bone marrow transplantation: Results of a placebo-controlled, double blind, randomized multicenter trial. Program and Abstracts of the XI Congress of the International Society for Human and Animal Mycology, Montreal. Abstract no. p S3114.Google Scholar
  191. 191.
    Slavin M, Bowden R, Osborne B, Adams R, Levenstein M, Feldman A, Meyers J. 1992. Fluconazole prophylaxis in marrow transplant recipients. Program and Abstracts of the 1992 Interscience Conference on Antimicrobial Agents in Chemotherapy. American Society for Microbiology, Washington DC, abstract no. 623, p 214.Google Scholar
  192. 192.
    Winston DJ, Chandrashekar, Lazarus HM, et al. 1993. Fluconazole prophylaxis of fungal infections in patients with leukemia. Ann Intern Med 118:495–503.PubMedGoogle Scholar
  193. 193.
    Anaissie E, Reuben A, Cunningham K, Bodey GP. 1990. Randomized trial of fluconazole vs. intravenous amphotericin B for antifungal prophylaxis in neutropenic patients with leukemia. Program and Abstracts of the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy. Atlanta, GA, October, Abstract no. 572, p 21.Google Scholar
  194. 194.
    Wingard JR, Merz, Rinaldi MG, Johnson TR, Karp JE, Sarai R. 1991. Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole. N Engl J Med 325:12740–1277.Google Scholar
  195. 195.
    Persons PA, Laughlin M, Tanner D, Perfect J, Guckerman JP, Hathorn JW. 1991. Fluconazole and Candida krusei fungemia. N Engl J Med 325:1315.PubMedGoogle Scholar
  196. 196.
    Tarn JY, Blume KG, Prober CG. 1992. Prophylactic fluconazole and Candida krusei infections [letter]. N Engl J Med 326:891.Google Scholar
  197. 197.
    Gondal et al. 1989 on p 234 in text.Google Scholar
  198. 198.
    Rex JH, Bennett JE, Sugar AM, Pappas PG, van der Horst CM, Edwards JE, Washburn RG, Scheid WM, Karchmer AW, Dine AP, Levenstein MJ, and Webb CD. 1994. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. N Engl J Med 331:1325–1330.PubMedGoogle Scholar
  199. 199.
    Sugar AM, Saunders C. 1988. Oral fluconazole as suppressive therapy of disseminated cryptococcosis in patients with acquired immunodeficiency syndrome. Am J Med 85:481–489.PubMedGoogle Scholar
  200. 200.
    Bozzette SA, Larsen RA, Chiu J, et al. 1991. A placebo-controlled trial of maintenance therapy with fluconazole after treatment of cryptococcal meningitis in the acquired immunodeficiency syndrome. N Engl J Med 324:580–584.PubMedGoogle Scholar
  201. 201.
    Saag MS, Powderly WG, Cloud GA, Robinson P, Grieco MH, et al. 1992. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. N Engl J Med 326:83–89.PubMedGoogle Scholar
  202. 202.
    Tucker RM, Galgiani JN, Denning DW, Hanson LH, Graybill JR, Sharkey K, Eckman MR, Salemi C, Libke R, Klein RA, Stevens DA. 1990. Treatment of coccidioidal meningitis with fluconazole. Rev Infect Dis 12(Suppl 3):S380–S389.PubMedGoogle Scholar
  203. 203.
    Kauffman CA, Bradley SF, Ross SC, Weber DR. 1991. Hepatosplenic candidiasis: Successful treatment with fluconazole. Am J Med 91:137–141.PubMedGoogle Scholar
  204. 204.
    Anaissie E, Bodey GP, Kantarjian H, David C, Barnett K, Bow E, Defelice R, Downs N, File T, Karam G, Potts D, Shelton M, Sugar A. 1991. Fluconazole therapy for chronic disseminated candidiasis in patients with leukemia and prior amphotericin B therapy. Am J Med 91:142–150.PubMedGoogle Scholar
  205. 205.
    Ryley JF, McGregor S, Wilson RG. 1988. Activity of ICI 195,739—a novel, orally active bistriazole—in rodent models of fungal and protozoal infections. Ann NY Acad Sci 544:310–328.PubMedGoogle Scholar
  206. 206.
    Fromtling RA. 1988. Overview of medically important antifungal azole derivatives. Clin Microbiol Rev 1:187–217.PubMedGoogle Scholar
  207. 207.
    Tucker RM, Hanson LH, Brummer E, Stevens DA. 1989. Activity of ICI 195,739, a new oral triazole, compared with that of ketoconazole in the therapy of experimental murine blastomycosis. Antimicrob Agents Chemother 33:573–575.PubMedGoogle Scholar
  208. 208.
    Barchiesi F, Colombo AL, McGough DA, Fothergill AW, Rinaldi MG. 1994. In vitro activity of DO870 against Candida albicans and Aspergillus spp. Abstracts of the 34th Interscience onference on Antimicrobial Agents in Chemotherapy. Orlando, Florida, October 4–7, 1994, abstract F199, p 255.Google Scholar
  209. 209.
    Najvar L, Bocanegra R, Luther M, Graybill J. 1994. Abstracts of the 34th Interscience Conference on Antimicrobial Agents in Chemotherapy. Orlando, Florida, October 4–7, abstract F201, p 255.Google Scholar
  210. 210.
    Lee JW, Lin C, Loebenberg D, Rubin M, Pizzo PA, Walsh TJ. 1989. Pharmacokinetics and tissue penetration of Sch 39304 in granulocytopenic and nongranulocytopenic rabbits. Antimicrob Agents Chemother 33:1932–1935.PubMedGoogle Scholar
  211. 211.
    Perfect JR, Wright KA, Hobbs MM, Durack DT. 1989. Treatment of experimental cryptococcal meningitis and disseminated candidiasis with Sch 39304. Antimicrob Agents Chemother 33:1735–1740.PubMedGoogle Scholar
  212. 212.
    Restrepo BI, Ahrens J, Graybill JR. 1989. Efficacy of Sch 39304 in murine cryptococcosis. Antimicrob Agents Chemother 33:1242–1246.PubMedGoogle Scholar
  213. 213.
    Walsh TJ, Lester-McCully C, Rinaldi MG, Wallace JE, Balis FM, Lee JW, Pizzo PA, Poplack DG. 1990. Penetration of Sch 39304, a new triazole, into cerebrospinal fluid of primates. Antimicrob Agents Chemother 34:1281–1284.PubMedGoogle Scholar
  214. 214.
    Lin C, Kim H, Lapiguera A, Loebenberg D, Miller GH, Symchowicz S. 1988. Comparative pharmacokinetics of Sch 39304 and fluconazole in mice, rabbits, S. monkeys, and C. monkeys. 28th Interscience Conference on Antimicrobial Agents and Chemotherapy, Los Angeles. Abstract no. 163.Google Scholar
  215. 215.
    Walsh TJ, Lee JW, Lecciones J, Kelly P, Peter J, Thomas V, Bacher J, Pizzo PA. 1990. Sch 39304 in prevention and treatment of disseminated candidiasis in persistently granulocytopenic rabbits. Antimicrob Agents Chemother 34:1560–1564.PubMedGoogle Scholar
  216. 216.
    Albert MM, Graybill JR, Rinaldi MG. 1991. Treatment of murine cryptococcal meningitis with an SCH 39304–amphotericin B combination. Antimicrob Agents Chemother 35:1721–1725.PubMedGoogle Scholar
  217. 217.
    Anaissie EJ, Kontoyiannis DP, Vartivarian S, Kantarjian HM, et al. 1993. Effectiveness of an oral triazole for opportunistic mold infections in patient with cancer: Experience with SCH393904. Clin Infect Dis 17:1022–1031.PubMedGoogle Scholar
  218. 218.
    Van Cutsem J, Van Gerven F, Janssen PAJ. 1988. R66905, a new potent broad-spectrum antifungal with topical, oral and parenteral activity. Rev Iberica Micologia 5(Suppl 1):Abstract 0–2.Google Scholar
  219. 219.
    Van Cutsem J, Van Gerven F, Janssen PAJ. 1989. Oral and parenteral therapy with saperconazole (R66905) of invasive aspergillosis in normal and immunocompromised animals. Antimicrob Agents Chemother 33:2063–2068.PubMedGoogle Scholar
  220. 220.
    Van Cutsem J, Van Gerven F, Janssen PAJ. 1989. Saperconazole, a new potent antifungal triazole: In vitro activity spectrum and therapeutic efficacy. Drugs Future 14:1187–1209.Google Scholar
  221. 221.
    Sawistowska-Schroder ET, Kerridge D, Perry H. 1984. Echinocandin inhibition of 1,3-b-D-glucan synthase from Candida albicans. Fed Eur Biochem Soc Lett 173:134–138.Google Scholar
  222. 222.
    Debono M, Abbott BJ, Turner JR, Howard LC, Gordee RS, Hunt AS, Barnhart M, Molloy RM, Willard KE, Fukuda DS, Butler TF, Zeckner DJ. 1988. Synthesis and evaluation of LY121019, a member of a series of semi-synthetic analogues of the antifungal lipopeptide echinocandin B. Ann NY Acad Sci 544:152–167.PubMedGoogle Scholar
  223. 223.
    Gordee RS, Zechner DJ, Ellis LF, Thakker AL, Howard LC. 1984. In vitro and in vivo anti-Candida activity and toxicology of LY121019. J Antibiot 37:1054–1065.PubMedGoogle Scholar
  224. 224.
    Gordee RS, Zeckner DJ, Howard LC, Alborn WE, Debono M. 1988. Anti-Candida activity and toxicology of LY121019, a novel semisynthetic polypeptide antifungal antibiotic. Ann NY Acad Sci 544:294–309.PubMedGoogle Scholar
  225. 225.
    Pfaller M, Riley J, Koerner T. 1989. Effects of cilofungin LY121019 on carbohydrate and sterol composition of Candida albicans. Eur J Clin Microbiol Infect Dis 8:1067–1070.PubMedGoogle Scholar
  226. 226.
    Hobbs M, Perfect JR, Durack D. 1988. Evaluation of in vitro antifungal activity of LY121019. Eur J Clin Microbiol Infect Dis 7:77–80.PubMedGoogle Scholar
  227. 227.
    Melchinger W, Mueller J. 1987. Studies of the in vitro sensitivity of yeast strains isolated from clinical specimens to LY121019, a new antifungal agent. Mykosen 30:605–608.PubMedGoogle Scholar
  228. 228.
    Schmatz DM, Romancheck MA, Pittarelli LA, Schwartz RE, Fromtling RA, Nollstadt KH, Vanmiddlesworth FL, Wilson, KE, Turner MJ. 1990. Treatment of Pneumocystis carinii pneumonia with 1,3-b-glucan synthesis inhibitors. Proc Nat Acad Med 87:5950–5954.Google Scholar
  229. 229.
    Black HR, Brier GL, Wolny JD, Dorrbecker SH. 1989. Pharmacology and pharmacokinetics of cilofungin. 29th Interscience Conference on Antimicrobial Agents and Chemotherapy, abstract no. 1357, Houston.Google Scholar
  230. 230.
    Lee JW, Kelly P, Lecciones J, Coleman D, Gordee R, Pizzo PA, Walsh TJ. 1990. Cilofungin (LY121019) shows nonlinear plasma pharmacokinetics and tissue penetration in rabbits. Antimicrob Agents Chemother 34:2240–2245.PubMedGoogle Scholar
  231. 231.
    Walsh TJ, Lee JW, Kelly P, Bacher J, Lecciones J, Thomas V, Lyman C, Coleman D, Gordee R, Pizzo PA. 1991. Antifungal effects of the nonlinear pharmacokinetics of cilofungin, a 1,3-β-glucan synthetase inhibitor, during continuous and intermittent intravenous infusions in treatment of experimental disseminated candidiasis. Antimicrobial Agents Chemother 35:1321–1328.Google Scholar
  232. 232.
    Balkovec JM, Black RM, Hammond ML, Heck JV, Zambias RA, Abruzzo G, Bartizal K, Puckett J, Trainor C, Schwartz R, McFadden DC, Nollstadt K, Pittarelli LA, Powles MA, Schmatz DM. 1991. Echinocandin analogues: Synthesis and in vivo efficacy of L-693,989 and other water soluble echinocandins in Candida and Pneumocystis rodent models. 31st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract no. 204.Google Scholar
  233. 233.
    Bartizal K, Abruzzo G, Trainor C, Puckett J, Ponticas S, Krupa D, Schmatz D, Nollstadt K, Schwartz R, Hammond M, Balkovec, J, Zambias R, Kropp H. 1991. 31st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract no. 206.Google Scholar
  234. 234.
    Hajdu R, Sundelof JG, Bartizal K, Abruzzo G, Trainor C, Thompson R, Kropp H. 1991. Comparative pharmacokinetics in four animal species of L-688,786 and its water soluble prodrug, L-693,989. 31st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract 209.Google Scholar
  235. 235.
    Suzuki S, Isono K, Nagutsu J, Mizutani T, Kawashimer C, Mizuno T. 1965. A new antibiotic, polyoxin A. J Antibiot 18:131–132.PubMedGoogle Scholar
  236. 236.
    Fiedler HP, Kurth R, Langharig J, Delzer J, Zahner H. 1982. Nikkomycins: Microbial inhibitors of chitin synthetase. J Chem Biotechnol 32:271–280.Google Scholar
  237. 237.
    Isono K, Nagatsu J, Kawashiwa Y, Suzuki S. 1985. Studies on polyoxins, antifungal antibiotics. I. Isolation and characterization of polyoxins A and B. Agricult Biolog Chem 29:848–854.Google Scholar
  238. 238.
    Gooday GW. 1988. Chitin metabolism: A target for antifungal and antiparasitic drugs. In: Borowski E, Shugar D, eds Molecular Aspects of Chemotherapy. New York: Pergamon Press, pp 175–185.Google Scholar
  239. 239.
    Payne JW, Shallow DA. 1985. Studies on drug targeting in the pathogenic fungus Candida albicans: Peptide transport mutants resistant to polyoxins, nikkomycins, and bacilysin. Fed Eur Microbiol Soc Microbiol Lett 28:55–60.Google Scholar
  240. 240.
    Hector RF, Zimmer BL, Pappagianis D. 1990. Evaluation of nikkomycins X and Z in murine models of coccidioidomycosis, histoplasmosis, and blastomycosis. Antimicrob Agents Chemother 34:587–593.PubMedGoogle Scholar
  241. 241.
    Smith et al. 1986.Google Scholar
  242. 242.
    Novider et al. 1983.Google Scholar
  243. 243.
    Petranyi G, Ryer NS, Stutz A. 1984. Allylamine derivatives: New class of synthetic antifungal agents inhibiting fungal squalene epoxidase. Science 224:1239–1241.PubMedGoogle Scholar
  244. 244.
    Shadomy S, Espinel-Ingroff A, Gebhart RJ. 1985. In vitro studies with SF 86–327, a new orally active allylamine derivative. Sabouraudia 23:125–132.PubMedGoogle Scholar
  245. 245.
    Smith EB. 1990. History of antifungals. J Am Acad Dermatol 23:776–778.PubMedGoogle Scholar
  246. 246.
    Ryder & Dupont 1985.Google Scholar
  247. 247.
    Villard V, Jones T. 1989. Clinical efficacy and tolerability of terbinafine (Lamisil)—a new topical and systemic fungicidal drug for treatment of dermatomycoses. Clin Exp Dermatol 14:124–127.Google Scholar
  248. 248.
    Petranyi G, Meingassner JG, Mieth H. 1987. Antifungal activity of the allylamine derivative terbinafine in vitro. Antimicrob Agents Chemother 31:1365–1368.PubMedGoogle Scholar
  249. 249.
    Jones TC, Villars VV. 1990. Terbinafine. In: Ryley JF, ed Chemotherapy of Fungal Diseases. Berlin: Springer-Verlag pp 483–503.Google Scholar
  250. 250.
    Oki T, Konishi M, Tomatsu K, Tomita K, Saitoh, Tsunakawa M, Nishio M, Miyaki T, Kawaguchi H. 1988. Pradimicin, a novel class of potent antifungal antibiotics. J Antibiot 41:1701–1704.PubMedGoogle Scholar
  251. 251.
    Tsunakawa M, Nishio M, Ohkuma H, Tsuno T, Konishi M, Naito T, Oki T, Dawaguchi H. 1988. A new antifungal antibiotic, BMY-28567. Structure elucidation. 28th Interscience Conference on Antimicrobial Agents and Chemotherapy, Los Angeles, abstract 1001.Google Scholar
  252. 252.
    Takeuchi T, Hara T, Naganawa H, Okada M, Hamada M, Umezawa H, Gomi S, Sezaki M, Kondo S. 1988. New antifungal antibiotics, benanomicins A and B from an Actinomycete. J Antibiot 41:807–811.PubMedGoogle Scholar
  253. 253.
    Oki T, Saitoh K, Tomatsu K, Tomita K, Konishi M, Kawaguchi H. 1988. Novel antifungal antibiotic BMY-28567. Ann NY Acad Sci 544:184–187.PubMedGoogle Scholar
  254. 254.
    Oki T, Tenmyo O, Hirano M, Tomatsu K, Kamei H. 1990. Pradimicins A, B and C: New antifungal antibiotics. II. In vitro and in vivo biological activities. J Antibiot 43:763–770.Google Scholar
  255. 255.
    Walsh TJ, van Cutsem J, Polak A, Graybill JR. 1992. Pathogenesis, immunomodulation, and antifungal therapy of experimental invasive candidiasis, histoplasmosis, and aspergillosis: Recent advances and concepts. J Med Vet Mycol 30(Suppl l):225–240.PubMedGoogle Scholar
  256. 256.
    Roilides 1994.Google Scholar
  257. 257.
    Bodey GP, Anaissie E, Gutterman J, Vadhan-Raj S. 1993. Role of granulocyte-macrophage colony stimulating factor as adjuvant therapy for fungal infection in patients with cancer. Clin Infect Dis 17:705–707.PubMedGoogle Scholar
  258. 258.
    Neumanaitis J, Mayers JD, Buckner CD, et al. 1991. Phase I trial of recombinant human macrophage colony-stimulating factor in patients with invasive fungal infections. Blood 4:907–913.Google Scholar
  259. 259.
    Anaissie E. 1992. Opportunistic mycoses in the immunocompromised host: Experience at a cancer center and review. Clin Infect Dis 14(Suppl 1):S43–S53.PubMedGoogle Scholar
  260. 260.
    Denning DW, Pappas PG, Kauffman CA, Hostetier JS, Lee JY, Stevens DA. 1991. Oral itraconazole therapy of invasive aspergillosis. 31st Interscientific Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract no. 1158.Google Scholar
  261. 261.
    Lee JW, Seibel NL, Amantea M, Whitcomb P, Pizzo PA, Walsh TJ. 1991. Safety, tolerance, and pharmacokinetics of fluconazole in children with neoplastic diseases. J Pediatr, xx:xxx-xxx.Google Scholar
  262. 262.
    Nair MG, Putnam AR, Mishra SK, Mulks MH, Taft WH, Keller JE, Miller JR, Zhu PP, Meinhart JD, Lynn DG. 1989. Faeriefungin: A new broad-spectrum antibiotic from Streptomyces griseus var. autotrophicus. J Nat Prod 52:797–809.PubMedGoogle Scholar
  263. 263.
    Mulks MH, Nair MG, Putnam AR. 1990. In vitro antibacterial activity of faeriefungin, a new broad-spectrum polyene macrolide antibiotic. Antimicrob Agents Chemother 34:1762–1765.PubMedGoogle Scholar
  264. 264.
    Roilides E, Pizzo PA. 1992. Modulation of host defenses by cytokines: Evolving adjuncts in prevention and treatment of serious infections in immunocompromised hosts. 15:508–523.Google Scholar
  265. 265.
    Ryder NS. 1988. Biochemical mode of action and enantiomeric selectivity of SDZ 89–485. Rev Iberica Micologia 5(Suppl l):Abst. P-154.Google Scholar
  266. 266.
    Steele RW, Abernathy RS. 1983. Systemic blastomycosis in children. Pediatr Infect Dis J 2:304–307.Google Scholar
  267. 267.
    Thaler M, Hathorn J, Skelton J, Rubin M, McKnight J, Pastakia R, Shawker T, Pizzo PA. 1988. Hepatic candidiasis in cancer patients. Ann Intern Med 108:88–100.PubMedGoogle Scholar
  268. 268.
    Van Cauteren H, Heykants J, DeCoster R, Cauwenbergh G. 1987. Itraconazole: Pharmacologic studies in animals and humans. Rev Infect Dis 9:S43–S46.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1995

Authors and Affiliations

  • Thomas J. Walsh
  • Caron A. Lyman

There are no affiliations available

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