European Journal of Epidemiology

, Volume 8, Issue 3, pp 407–421 | Cite as

Drug resistance in human pathogenic fungi

  • K. Iwata


Since the therapy of the mycoses, particularly the systemic mycoses, is relatively long-term in nature, emergence of resistance to antifungal drugs during the treatment of period would be of considerable clinical importance. However, most reports of resistance to antifungal agents among human pathogenic fungi indicate that naturally-occurring resistance is very rare, and that the induction of resistant mutants or variants is much more difficult to achieve in vitro and in vivo than with bacteria. As a matter of fact, amphotericin B and some other classic antifungals have not as yet posed a broadly significant problem relative to drug resistance despite their widespread and frequent use. Fungal resistance has thus received little attention, in contrast to the critical importance of bacterial resistance frequently caused by a variety of antibacterial chemotherapeutic agents, until a single exception to this generalization arose with the advent of flucytosine. This new development has aroused great interest in the problem of fungal resistance among the scientists involved with medical mycology. It is generally believed that fungi, like bacteria, are intrinsically capable of developing resistance to antifungal agents. As illustrated by flucytosine, inherently resistant mutants to antifungals occur within sensitive strains of human pathogenic fungi with significant frequency. Given the relatively high degree of such primary resistance, these mutants should develop secondary resistance during therapy, thus resulting in considerable limitations in the clinical usefulness of the antifungals. Virtually, all unsuccessful cases of mycoses treated with some of the recently exploited antifungal drugs, albeit scarce to date, would obviously be attributable to the occurrence of secondary resistance. The exploitation of new antifungal drugs thus requires investigations of their resistance as one of the most important research projects to be undertaken before receiving approval for use on humans. This paper reviews from various aspects the literature on resistance to various classic and novel antifungal agents among human pathogenic fungi. The resistance of some nonpathogenic fungi to these agents will also be described from genetic and biochemical points of view.

Key words

Drug resistance Human pathogenic fungi Antifungal agents 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    ArroyoJ., MedoffG. and KobayashiG.S. (1977): Therapy of murine aspergillosis with amphotericin B in combination with rifampin or 5-fluorocytosine -Antimicrob. Agents Chemother. 11: 21–25.Google Scholar
  2. 2.
    ArtisW.M., BonnieM., OdleB.M. and JonesH.E. (1981): Griseofulvin-resistant dermatophytosis correlates with in vitro resistance - Arch. Dermatol. 117: 16–19.Google Scholar
  3. 3.
    AtharM.A. (1969): A study of the effects of some polyene antibiotics on Candida sp. - Ph.D. Thesis -University of London - England.Google Scholar
  4. 4.
    AtharM.A. and WinnerH.I. (1971): The development of resistance by Candida species to polyene antibiotics in vitro - J. Med. Microbiol. 4: 505–517.Google Scholar
  5. 5.
    AtkinsonG.W. and IsraelH.J. (1973): 5-Fluorocytosine treatment of meningeal and pulmonary aspergillosis - Am. J. Med. 55: 496–504.Google Scholar
  6. 6.
    AugerP., DumasC. and JolyJ. (1979): A study of 666 strains of Candida albicans: correlation between serotype and susceptibility to 5-fluorocytosine - J. Infect. Dis. 139: 590–594.Google Scholar
  7. 7.
    AytounR.S.C., CampbellA.H., NapierE.J. and SeilerD.A.L. (1960): Mycological aspects of the action of griseofulvin against dermatophytes - Arch. Dermatol. 81: 650–656.Google Scholar
  8. 8.
    BaierR. and PuppelH. (1978): Antimykotika-Empfindlichkeit von Hefen aus klinischem Untersuchungsmaterial im Blättchendiffusiontest -Dt. med. Wschr. 103: 1112–1116.Google Scholar
  9. 9.
    BeggsW.M., AndrewF.A. and SarosiG.A. (1977): Evidence for sequential action of amphotericin B and 5-fluorocytosine on Candida albicans ATCC 11 651 -Res. Commun. Chem. Pathol. and Pharmacol. 16: 575–580.Google Scholar
  10. 10.
    BeggsW.H., SarosiG.A. and AndrewsF.A. (1974): Synergistic action of amphotericin B and rifampin on Candida albicans - Am. Rev. Resp. Dis. 110: 671–673.Google Scholar
  11. 11.
    BeggsW.H., SarosiG.A. and SteelN.M. (1976): Inhibition of potentially pathogenic yeastlike fungi by clotrimazole in combination with 5-fluorocytosine or amphotericin B - Antimicrob. Agents Chemother. 9: 863–865.Google Scholar
  12. 12.
    BeggsW.M., SarosiG.A. and WalkerM.I. (1976): Synergistic action of arnphotericin B and rifampin against Candida species - J. Infect. Dis. 133: 206–209.Google Scholar
  13. 13.
    BennetJ.E. (1977): Drugs 5 years later: Flucytosine -Ann. Intern. Med. 86: 319–322.Google Scholar
  14. 14.
    BennetJ.E., PlempelM., StevensD.A. and ScholerH.J. (1978): Chemotherapy of fungal diseases - In: Siegenthaler W. and Luthy R. eds. Current Chemotherapy, Proc. 10th International Congress of Chemotherapy, Zurich, 1977, Vol. 1, American Society for Microbiology, Washington, D.C., pp. 53–55.Google Scholar
  15. 15.
    BergyM.E. and EbleT.E. (1968): The filipin complex -Biochemistry 7: 653–658.Google Scholar
  16. 16.
    BernhardtH. and KnokeM. (1976): Resistenzprobleme bei Schleimhaut- und Organmykosen -Ber. Ges. innere Med. 10: 252–254.Google Scholar
  17. 17.
    BlockE.R. and BennetJ.E. (1973): The combined effect of 5-fluorocytosine and arnphotericin B in the therapy of murine cryptococcosis - Proc. Soc. Exp. Biol. Med. 142: 476–480.Google Scholar
  18. 18.
    BlockE.R. and BennetJ.E. (1974): 5-Fluorocytosine resistance in Candida albicans infections in man -Am. Rev. Resp. Dis. 109: 723–724.Google Scholar
  19. 19.
    BlockE.R., JenningsA.E. and BennetJ.E. (1973): 5-Fluorocytosine resistance in Cryptococcus neoformans- Antimicrob. Agents Chemother. 3: 649–656.Google Scholar
  20. 20.
    BodenhoffJ. (1968a): Resistance studies of Candida albicans, with special reference to two patients subjected to prolonged treatment - Odont. Tidskr. 76: 279–294.Google Scholar
  21. 21.
    BodenhoffJ. (1968b): Development of strains of Cryptococcus neoformans resistant to nystatin, amphotericin B, trichomycin and polymyxin B - Acta Path. Microbiol. Scand. 73: 572–582.Google Scholar
  22. 22.
    BodenhoffJ. (1969): Development of strains of genus Candida and genus Torulopsis resistant to antimycotics - Acta Path. Microbiol. Scand. 75: 622–630.Google Scholar
  23. 23.
    BondruI. (1969): De la resistance des Candida albicans à la nystatine - J. Pharm. belg. 24: 162–185.Google Scholar
  24. 24.
    BorgersM. (1987): Changes in fungal ultrastructure after Raconazole treatment - In: Vanden Bossche H., Mackenzie D.W.R. and Cauwenbergh eds. Aspergillus and Aspergillosis - Plenum - New York -pp. 193–206.Google Scholar
  25. 25.
    BorgersM. and Van deVenM.-A. (1987): Degenerative changes in fungi after itraconazole treatment - Rev. Infect. Dis. 9 Suppl. 1: S33-S42.Google Scholar
  26. 26.
    BrinkmannF. (1981): Sekundäre Sensibilitätsänderung von Candida albicans gegen 5-Fluoro-cytosin (5-FC) in vitro: Vergleich von fünf Methoden im Hinblick auf Routineuntersuchungen - Z. Hautkr. 56: 1255–1263.Google Scholar
  27. 27.
    CapekA. and SimekA. (1972): Antimicrobial agents. 115. Content of ergosterol and the problem of transient resistance of dermatophytes - Folia microbiol. 17: 239–240.Google Scholar
  28. 28.
    CapekA., SimekA., LeinerJ. and WeichetJ. (1970): Antimicrobial agents. 6. Antimycotic activity and problems of reistance - Folia microbiol. 15: 314–317Google Scholar
  29. 29.
    CartwrightR.Y., ShaldonC. and HallG.H. (1972): Urinary candidiasis after renal transplantation - Br. Med. J. 2: 351.Google Scholar
  30. 30.
    CorradoM.L., WeitzmanI., StanekA., GoetzR. and AgyareE. (1980): Subcutaneous infection with Phialophora richardsiae and its susceptibility to 5-fluorocytosine, arnphotericin B and miconazole- Sabouraudia 18: 97–104.Google Scholar
  31. 31.
    CrouzetM., PerrotM., NogueiraM. and BegueretJ. (1978): Genetic and biochemical analysis of cycloheximide resistance in the fungus Podospora anserina - Biochem. Genet. 16: 271–286.Google Scholar
  32. 32.
    DaviesR.R., EverallJ.D. and HamiltonE. (1967): Mycological and clinical evaluation of griseofulvin for chronic onychomycosis - Br. Med. J. iii: 464–468.Google Scholar
  33. 33.
    DaviesR.R. and SavageM.A. (1974): Observations on 5-fluorocytosine and Candida albicans - Sabouraudia 12: 302–308.Google Scholar
  34. 34.
    DefeverK.S., WhelanW.L., RogersA.L., BenekeE.S., VeselenakJ.M. and SoilD.R. (1982): Candida albicans resistance to 5-fluorocytosine: frequency of partially resistant strains among clinical isolates - Antimicrob. Agents Chemother. 22: 810–815.Google Scholar
  35. 35.
    DekkerJ. (1985): The development of resistance to fungicides. In: Hutson D.H. and Roberts T.R. eds., Progress in Pesticide Biochemistry and Toxicology -John Wiley & Sons - New York - N.Y. - Vol. 4: 165–218.Google Scholar
  36. 36.
    DermoumiH. (1982): Antimykotika - Empfindlichkeit bei klinisch bedeutsamen Helfen und Schimmelpilzen im Hemmholftert - Mykosen 25: 109–117.Google Scholar
  37. 37.
    DiasioR.B., BennettJ.E. and MyersC.E. (1978): The mode of action of 5-fluorocytosine - Biochem. Pharmac. 27: 703–707.Google Scholar
  38. 38.
    DonovikR., PansyF.E., StoutH.A., StanderH., WeinsteinM.J. and GoldW. (1955): Some in vitro characteristics of nystatin (mycostatin) - In: Sternberg T.H. and Newcomer V.D. eds. International Symposium on therapy of Fungus Diseases, Little, Brown & Co. - Boston - pp. 875–883.Google Scholar
  39. 39.
    Drouhet E. (1973): Chemotherapy of systemic and deep mycoses due to opportunistic fungi. In: Daikos, G.K. ed. - Progress in Chemotherapy — Proc. 8th Int. Congr. Chemother. - Athens - Vol. 1, pp. 875–883.Google Scholar
  40. 40.
    DrouhetE., Ktenidou-KartalisS. and ImprovisiL. (1976a): Phenotypes de resistance a la 5-fluorocytosine chez Cryptococcus neoformans - Bull. Soc. fr. Mycol. med. 5: 17–20.Google Scholar
  41. 41.
    DrouhetE., Ktenidou-KartalisS. and ImprovisiL. (1976b): Phénotypes de résistance aux 5-fluoropyrimidines chez les Torulopsis - Bull. Soc. fr. Mycol. méd. 5: 91–94.Google Scholar
  42. 42.
    DrouhetE., Mercier-SoucyL. and MontplaisirS. (1975): Sensibilité et résistance des levures pathogéenes aux 5-fluoropyrimidines. 1. Relation entre les phénotypes de résistance à la 5-fluorocytosine, le sérotype de Candida albicans et Pécologie de différentes espèces de Candida d'origine humaine - Ann. Microbiol. (Inst. Past.) 126B: 25–29.Google Scholar
  43. 43.
    DrutzD.J. and LehrerR.I. (1978): Development of amphotericin B-resistant Candida tropicalis in a patient with defective leukocyte function - Am. J. Med. Sci. 276: 77–92.Google Scholar
  44. 44.
    FasoliM.O.F., KerridgeD. and RyleyJ.F. (1990): Pathogenicity of 5-fluorocytosine resistant strains of Candida albicans - J. Med. Vet. Mycol. 28: 27–34.Google Scholar
  45. 45.
    FassR.J. and PerkinsR.L. (1974): 5-Fluorocytosine in the treatment of cryptococcal and Candida mycoses -Ann. Intern. Med. 74: 535–539.Google Scholar
  46. 46.
    FeiginR.D., ShacklefordP.G., EisenS., SpitlerL.E., PickeringL.K. and AndersonP.C. (1974): Treatment of mucocutaneous candidiasis with transfer factor -Pediatrics 53: 63–70.Google Scholar
  47. 47.
    Fields B.T., Meredith W.R., Galbraith J.E. and Hardin H.F. (1974): Studies with amphotericin B and 5-fluorocytosine in aspergillosis — Clin. Res. 22: 32A.Google Scholar
  48. 48.
    FirkinF.C. (1974): Therapy of deep-seated fungal infections with 5-fluorocytosine - Aust. N.Z. J. Med. 4: 462–467.Google Scholar
  49. 49.
    FisherB.K., SmithJ.G., CrounseR.G., RuthF.J.Jr. and BlankH. (1961): Verrucous epidermophytosis: its response and resistance to griseofulvin - Arch. Dermatol. 84: 375–380.Google Scholar
  50. 50.
    FlandroisJ.P. (1975): Etat actuel de la sensibilité a la fluoro-5-cytosine des levures du genre Candida isolées chez l'homme - Med. Mal. infect. 5: 351–356.Google Scholar
  51. 51.
    FordJ.H. and KlomparensW. (1960): Cycloheximide (Acti-dione) and its non-agricultural uses - Antibiot. Chemother. 10: 682–687.Google Scholar
  52. 52.
    FrybergM., OehIschlagerA.C. and UnrauA.M. (1974): Sterol biosynthesis in antibiotic-resistant yeast: nystatin - Arch. Biochem. Biophys. 160: 83–89.Google Scholar
  53. 53.
    FrybergM., OehlschlagerA.C. and UnrauA.M. (1976): Sterol biosynthesis in antibiotic sensitive and resistant Candida - Arch. Biochem. Biophys. 173: 171–177.Google Scholar
  54. 54.
    GaleE.F. (1974): The release of potassium ions from Candida albicans in the presence of polyene antibiotics - J. Gen. Micro. 80: 451–465.Google Scholar
  55. 55.
    GaleE.F., AlisonM., JohnsonD.M., KerridgeD. and MilesE.A. (1978): Phenotypic resistance to amphotericin B in Candida albicans: the role of reduction - J. Gen. Microbiol. 109: 191–204.Google Scholar
  56. 56.
    GaleE.F., JohnsonA.M. and KerridgeD. (1977): The effects of aeration and metabolic inhibitors on resistance to amphotericin in starved cultures of Candida albicans - J. Gen. Microbiol. 99: 77–84.Google Scholar
  57. 57.
    GaleE.F., JohnsonA.M., KerridgeD. and KohT.Y. (1975): Factors affecting the changes in amphotericin sensitivity of Candida albicans during growth - J. Gen. Microbiol. 87: 20–36.Google Scholar
  58. 58.
    GaleE.F., IngramJ, KerridgeD., NotarioY. and WaymanF. (1980): Reduction of amphotericin resistance in stationary phase cultures of Candida albicans by treatment of enzymes - J. Gen. Microbiol. 117: 383–391.Google Scholar
  59. 59.
    GarganiG., CampisiE. and FaggiE. (1976): Fréquence et caractéristiques des souches de C. albicans résistantes à la 5-fluorocytosine - Bull. Soc. fr. Mycol. méd. 5: 95–97.Google Scholar
  60. 60.
    Garrique I.L., Sande M.A. and Utz J.P. (1973): Combined amphotericin B — flucytosine chemotherapy in human cryptococcosis — Abst. 13th Intersci. Conf. Antimicrob. Agents Chemother. Washington, D.C. — No. 239.Google Scholar
  61. 61.
    GordonM.A., HolzmanR.S., SenterH., LapaE.W. and KupersmithM.J. (1976): Aspergillus oryzae meningitis- J. Am. Med. Ass. 235: 2122–2123.Google Scholar
  62. 62.
    GreeneW.H. and WiernikP.H. (1972): Candida endophthalmitis, successful treatment in a patient with acute leukemia - Am. J. Ophthal. 74: 1100–1102.Google Scholar
  63. 63.
    GrensonM. (1969): The utilization of exogenous pyrimidines and the recycling of uridine-5′-phosphate derivatives in Saccharomyces cerevisiae, as studied by means of mutants affected in pyrimidine uptake and metabolism - Eur. J. Biochem. 11: 249–260.Google Scholar
  64. 64.
    64.GrillotR., SlavovR., GrayralJ.P., BuissièreJ. and Ambroise-ThomasP. (1975): Sensibilité de 250 souches de levures á la flucytosine et a l'ámphotéricin B - Bull. Soc. fr. Mycol. méd. 4:173–176.Google Scholar
  65. 65.
    GrinE.I., NadazdinM. and OzegovicL. (1965): Investigations of dermatophyte sensitivity to griseofulvin - Acta Derm. Venereol. 45: 283–287.Google Scholar
  66. 66.
    HalkinH., RavidM., ZulmanJ. and ReichertN. (1974): Cryptococcal meningitis treated with 5-fluorocytosine and amphotericin B - Israel J. Med. Sci. 10: 1048–1052.Google Scholar
  67. 67.
    HamiltonJ.D. and EliottD.M. (1975): Combined activity of amphotericin B and 5-fluorocytosine against Cryptococcus neoformans in vitro and in vivo in mice - J. Infect. Dis. 131: 129–137.Google Scholar
  68. 68.
    Hamilton-MillerJ.M.T. (1972a): A comparative in vitro study of amphotericin B, clotrimazole and 5-fluorocytosine against clinically isolated yeasts -Sabouraudia 10: 276–283.Google Scholar
  69. 69.
    Hamilton-MillerJ.M.T. (1972b): Physiological properties of mutagen-induced variants of Candida albicans resistant to polyene antibiotics - J. Med. Microbiol. 5: 425–440.Google Scholar
  70. 70.
    Hamilton-MillerJ.M.T. (1972c): Sterols from polyene resistant mutants of Candida albicans - J. Gen. Microbiol. 73: 201–203.Google Scholar
  71. 71.
    HammondS.M. and KligerB.N. (1976): Mode of action of the polyene antibiotic candidin: binding factors in the wall of Candida albicans - Antimicrob. Agents Chemother. 9: 561–568.Google Scholar
  72. 72.
    HantschkD. and GoetzH. (1981): Griseofulvin resistance - Int. Dermatol. 18: 249–260.Google Scholar
  73. 73.
    HarderE.J. and HermanP.E. (1975): Treatment of fungal infections with flucytosine - Arch. Intern. Med. 135: 1269–1270.Google Scholar
  74. 74.
    HebekaE.X. and SolotorovskyM. (1962): Development of strains of Candida albicans resistant to candidin - J. Bacteriol. 84: 237–241.Google Scholar
  75. 75.
    HebekaE.K and SolotorovskyM. (1965): Development of resistance to polyene antibiotics in Candida albicans - J. Bacteriol. 89: 1533–1539.Google Scholar
  76. 76.
    HejzlarM. and VymolaF. (1970): Comparative study of pimaricin and fungicidin activity in vitro - J. Hyg. Epidem. Microbiol. Immun. 14: 211–213.Google Scholar
  77. 77.
    HitchcockC.A., Barrett-BeeK.J. and RussellN.J. (1986): The lipid composition of azole-sensitive and azole-resistant strains of Candida albicans - J. Gen. Microbiol. 132: 2421–2431.Google Scholar
  78. 78.
    HitchcockC.A., Barrett-BeeK.J. and RussellN.J. (1987a): Inhibition of 14 α — sterol demethylase activity in Candida albicans Darlington does not correlate with resistance to azole - J. Med. Vet. Mycol. 25: 329–333.Google Scholar
  79. 79.
    HitchcockC.A., Barrett-BeeK.J. and RussellN.J. (1987b): The lipid composition and permeability to azole of an azole- and polyene-resistant mutant of Candida albicans - J. Med. Vet. Mycol. 25: 29–37.Google Scholar
  80. 80.
    HoeprichP.D., IngrahamJ.L., KlekerE. and WinshipM.J. (1974): Development of resistance to 5-fluorocytosine in Candida paropsilosis during therapy- J. Infect. Dis. 130: 112–118.Google Scholar
  81. 81.
    HolbrookW.P. and KippaxR. (1979): Sensitivity of Candida albicans from patients with chronic candidiasis - Postgrad. Med. J. 55: 692–694.Google Scholar
  82. 82.
    HoltR.J. (1974): Recent developments in antimycotic chemotherapy - Infection 2: 95–107.Google Scholar
  83. 83.
    HoltR.J. and AzmiA. (1978): Miconazole-resistant Candida - Lancet i: 50–51.Google Scholar
  84. 84.
    HoltR.J. and NewmanR.L. (1972a): Laboratory assessment of the antimycotic drug clotrimazole - J. Clin. Path. 25: 1089–1097.Google Scholar
  85. 85.
    HoltR.J. and NewmanR.L. (1972b): Urinary candidiasis after renal transplantation - Br. Med. J. 2: 714–715.Google Scholar
  86. 86.
    HoltR.J. and NewmanR.L. (1972c): The treatment of urinary candidosis with the oral and antifungal drugs 5-fluorocytosine and clotrimazole - Devl. Med. Child Neurol. 14 Suppl. 27: 70–78.Google Scholar
  87. 87.
    HorneM.J., TaylorR.F., WilliamsR. and ZylstraW. (1975): Candida endophthalmitis - Med. J. Aust. 62: 170–172.Google Scholar
  88. 88.
    HorsburghC.R. and KirkpatrikC.H. (1983): Longterm therapy of chronic mucocutaneous candidosis with ketoconazole: experience with twenty-one patients - Am. J. Med. 74: 23–29.Google Scholar
  89. 89.
    HorsburghC.R., KirkpatrikC.H. and TeutschC.B. (1982): Ketoconazole and the liver - Lancet i: 23–29.Google Scholar
  90. 90.
    HsuK.S. (1963): The genetic basis of actidione resistance in Neurospora - J. Gen. Microbiol. 32: 341–347.Google Scholar
  91. 91.
    HsuChenC-C. and FeingoldD.S. (1974): Two types of resistance to polyene antibiotics in Candida albicans- Nature 251: 656–659.Google Scholar
  92. 92.
    HughesC.E., BennetR.L., TunaI.C. and BeggsW.H. (1988): Activities of fluconazole (UK 49,858) and ketoconazole against ketoconazole-susceptible and —resistant Candida albicans - Antimicrob. Agents Chemother. 32: 209–212.Google Scholar
  93. 93.
    HutletJ (1976): Evaluation of 2 methods of in vitro susceptibility testing of Candida albicans against 5-fluorocytosine- Can. J. Med. Technol. 38: 169–172.Google Scholar
  94. 94.
    IbrahimM.A.K. and CoddingtonA. (1976): Genetic studies on cycloheximide-resistant strains of Schizosaccharomyces pombe - Heredity 37: 179–191.Google Scholar
  95. 95.
    IwataK., YamashitaT., OhsumiM., BabaM., NaitoN., TakiA. and YamadaN. (1990): Comparative morphological and biological studies on the itraconazole- and ketoconazole-resistant mutans of Cryptococcus neoformans - J. Med. Vet. Mycol. 28: 77–90.Google Scholar
  96. 96.
    IwataK., YamashitaT. and UeharaH. (1989): In vitro and in vivo activity of piritetrate (M-732), a new antidermatophytic thiocarbamate - Antimicrob. Agents Chemother. 33: 2118–2125.Google Scholar
  97. 97.
    IwataK., YamashitaT., UeharaH. and NozawaY. (1990): In vitro thiocarbamate resistance of Trichophyton mentagrophytes - Chemotherapy (Tokyo) 38: 437–443.Google Scholar
  98. 98.
    JohnsonE.M., RichardsonM.D. and WarnokD.W. (1984): In vitro resistance to imidazole antifungals in Candida albicans - J. Antimicrob. Chemother. 13: 547–588.Google Scholar
  99. 99.
    JundR. and LacrouteF. (1970): Genetic and physiological aspects of resistance to 5-fluoropyrimidines in Saccharomyces cerevisiae - J. Bacteriol. 102: 607–615.Google Scholar
  100. 100.
    JundR. and LacrouteF. (1974): Génétique et physiologie de la résistance aux 5-fluoropyrimidines chez Saccharomyces cerevisiae - Bull. Soc. fr. Mycol. Méd. 3: 5–8.Google Scholar
  101. 101.
    KamalamA., YesudianP. and ThambiahA.S. (1977): An unusual presentation of Trichophyton violaceum infection - Br. J. Dermatol. 96: 205–209.Google Scholar
  102. 102.
    KauffmanC.A. and TanJ.S. (1974): Torulopsis glabrata renal infection - Am. J. Med. 57: 217–224.Google Scholar
  103. 103.
    KitaharaM., SethV.K., MedoffG. and KobayashiG.S. (1976): Activity of amphotericin B, 5-fluorocytosine and rifampicin against six clinical isolates of Aspergillus - Antimicrob. Agents Chemother. 9: 915–919.Google Scholar
  104. 104.
    KobayashiG.S., CheungS.C., SchlessingerD. and MedoffG. (1974): Effects of rifamycin derivatives, alone and in combination with amphotericin B, against Histoplasma capsulatum - Antimicrob. Agents Chemother. 5: 16–18.Google Scholar
  105. 105.
    KobayashiG.S., MedoffG., SchlessingerD., KwanC.N. and MusserW.E. (1972): Amphotericin B potentiation of rifampicin as an antifungal agent against the yeast phase of Histoplasma capsulatum -Science 177: 709–710.Google Scholar
  106. 106.
    KostelnikF.V. and FremountH.N. (1976): Mycotic tubo-ovarian abscess associated with intrauterine device - Am. J. Obstet, Gynec. 125: 272–274.Google Scholar
  107. 107.
    KostialaA.A.I. and KostialaI. (1984): Susceptibility of fungi in mouthrise specimens from patients with haematological malignancies - J. Med. Microbiol. 18: 249–254.Google Scholar
  108. 108.
    KwanC.N., MedoffG., KobayashiG.S., SchlessingerD. and RaskasH.J. (1972): Potentiation of the antifungal effects of antibiotics by amphotericin B -Antimicrob. Agents Chemother. 2: 61–65.Google Scholar
  109. 109.
    LampenJ.O., MorganE.R. and SlocumA. (1957): Effect of nystatin on the utilization of substrates by yeast and other fungi - J. Bacteriol. 74: 297–302.Google Scholar
  110. 110.
    LauerB.A., RellerL.B. and SchroterG.P.J. (l978): Susceptibility of Aspergillus to 5-fluorocytosine and amphotericin B alone and in combination - J. Antimicrob. Chemother. 4: 375–380.Google Scholar
  111. 111.
    LenhartK (1970): Griseofulvin-resistant mutants in dermatophytes: II. Physiological and genetic studies- Mykosen 13: 139–144.Google Scholar
  112. 112.
    Littman M.L., Pisano M.A. and Lancaster R.M. (1958): Induced resistance of Candida species to nystatin and amphotericin B - Antibiot. Ann., 1957–1958, 981–987.Google Scholar
  113. 113.
    LonesG.W. and PeacockC.L. (1959): Alterations in Candida albicans during growth in the presence of amphotericin B - Antibiot. Chemother. 9: 535–540.Google Scholar
  114. 114.
    LopesC.F., ResendeM.A., AlvarengaR.J., MoreiraY.K. and FerreiraI. (1978): 5-Fluorocytosine in the treatment of chromomycosis, in current chemotherapy, Proc. 10th Int. Congr., chemother., Zurich. In: Siegenthaler W. and Lilthy R. eds. American Society of Microbiology - Ann. Arbor. Vol. 1: pp. 219–220.Google Scholar
  115. 115.
    MarksM.I., SteerP. and EickoffT.C. (1971): In vitro sensitivity of Torulopsis glabrata to amphotericin B, 5-fluorocytosine and clotrimazole - Appl. Microbiol. 22: 93–96.Google Scholar
  116. 116.
    MedoffG., ComfortM. and KobayashiG.S. (1971): Synergistic action of amphotericin B and 5-fluorocytosine against yeast-like organisms - Proc. Soc. Exp. Biol. Med. 138: 571–574.Google Scholar
  117. 117.
    MedoffG., KobayashiG.S., KwanC.N., SchlessingerD. and VenkovP. (1972): Potentiation of rifampin and 5-fluorocytosine as antifungal antibiotics by amphotericin B - Proc. Natn. Acad. Sci. USA 69: 196–199.Google Scholar
  118. 118.
    MeyersB.R., LiebermanT.W. and FerryA.P. (1973): Candida endophthalmitis complicating candidemia- Ann. Intern. Med. 79: 647–653.Google Scholar
  119. 119.
    MichaelidesP., RosenthalS.A., SulzbergerM.B. and WittenY.R. (1961): Trichophyton tonsurans infection resistant to griseofulvin: a case demonstrating clinical and in vitro resistance - Arch. Dermatol. 83: 988–990.Google Scholar
  120. 120.
    Michalska-TrenknerE. (1970): Induced resistance of C. albicans strains to sodium salt of N-succinyl perimycin - Chemotherapy (Basel) 15: 19–25.Google Scholar
  121. 121.
    MolzahnS. and WoodsR.A. (1972): Polyene resistance and the isolation of sterol mutants in Saccharomyces cerevisiae - J. Gen. Microbiol. 72: 339–348.Google Scholar
  122. 122.
    MontgomerieJ.Z., EdwardsJ.E.Jr. and GuzeL.B. (1975): Synergism of amphotericin B and 5-fluorocytosine for Candida species - J. Infect. Dis. 132: 82–86.Google Scholar
  123. 123.
    MontplaisirS., DrouhetE. and Mercier-SoucyL. (1975): Sensitivity and resistance of pathogenic yeasts to 5-fluorocytosine. II. Mechanisms of resistance to 5-fluorocytosine and 5-fluorouracil -Ann. Microbiol. (Inst. Past.) 126B: 41–49.Google Scholar
  124. 124.
    NeuhäsuserA., KlingmüllerE. and KaudewitzF. (1970): Selektion Actidion-resistenter Mutanten bei Neurospora crassa - Molec. Gen. Genet. 106: 180–194.Google Scholar
  125. 125.
    NormanA.W., SpielvogelA.M. and WongR.C. (1976): Polyene antibiotic-sterol interaction -Adv. Lipid Res. 14: 127–170.Google Scholar
  126. 126.
    NormarkS. and SchönebeckJ. (1972): In vitro and in vivo 5-fluorocytosine resistance in Candida albicans and Torulopsis glabrata - Antimicrob. Agents Chemother. 2: 114–121.Google Scholar
  127. 127.
    NorthJ. (1982): A dominance modifier for cycloheximide resistance in Coprinus cinereus - J. Gen. Microbiol. 128: 2747–2753.Google Scholar
  128. 128.
    NotarioV., GaleE.F., KerridgeD. and WaymanF. (1982): Phenotypic resistance to amphotericin B in Candida albicans: relationship to glucan metabolism - J. Gen. Microbiol. 128: 761–777.Google Scholar
  129. 129.
    PankeyG.A., LockwoodW.R. and MontalvoJ.M. (1970): 5-Fluorocytosine: a replacement for amphotericin B in the treatment of Candida and Cryptococcus neoformans infections? - J. La St. Med. Soc. 122: 365–369.Google Scholar
  130. 130.
    PappagianisD., CollinsM.S., HectorR. and RemingtonJ. (1979): Development of resistance to amphotericin B in Candida lusitaniae infecting a human - Antimicrob. Agents Chemother. 16: 123–126.Google Scholar
  131. 131.
    PatelP.V. and JohnstonJ.R. (1968): Dominant mutation for nystatin resistance in yeast - Appl. Microbiol. 16: 164–165.Google Scholar
  132. 132.
    PerrotM.O., GrillotR. and Ambroise-ThomasP. (1977): Répartition dans l'organisme et sensibilité à la 5-fluorocytosine des 2 sérotypes de Candida albicans, étude de 680 souches - Bull. Soc. fr. Mycol. Méd. 6: 305–309.Google Scholar
  133. 133.
    PerryH.O. and UlrichJ.A. (1955): Laboratory studies on endomycin, with special reference to its antifungal effect against Candida albicans - J. Invest. Dermatol. 24: 623–631.Google Scholar
  134. 134.
    PerssonM., WinbladB., ÅnsênS. and SchönebeckJ. (1978): Pathogenicity in mice of strains of Candida albicans with different in vitro sensitivity to 5-fluorocytosine- Scand. J. Infect. Dis. 10: 91–92.Google Scholar
  135. 135.
    PlempelM. and BartmannK. (1972): Experimental studies on the antimycotic action of clotrimazole (Canesten) in vitro and after local application in vivo- Drugs Germ. 15: 103–120.Google Scholar
  136. 136.
    PolakA. (1974): Détermination du synergisme entre la 5-fluorocytosine et l'amphotéricin B au moyen de différents modèles in vitro et in vivo - Bull. Soc. fr. Mycol. Méd. 3: 175–178.Google Scholar
  137. 137.
    PolakA. (1978): Synergism between 5-fluorocytosine and polyene antibiotics - Pathol. Microbiol. 42: 423–425.Google Scholar
  138. 138.
    PolakA. and ScholerH.J. (1975): Mode of action of 5-fluorocytosine and mechanisms of resistance -Chemotherapy (Basel) 21: 113–130.Google Scholar
  139. 139.
    PolakA. and ScholerH.J. (1976): Combination of amphotericin B and 5-fluorocytosine - In: Williams J.D. and Geddes A.M. eds. Chemotherapy, Proc. 9th International Congress of Chemotherapy, London, 1975, Plenum Press, New York, Vol. 6, pp. 137–142.Google Scholar
  140. 140.
    PortilloF. and GancedoC. (1985): Mitochondrial resistance to miconazole in Saccharomyces cerevisiae- Molec. Gen. Genet. 199: 495–499.Google Scholar
  141. 141.
    RabinovichS., ShawB.D., BryantT. and DontaS.T. (1974): Effect of 5-fluorocytosine and amphotericin B on Candida albicans infection in mice - J. Infect. Dis. 130: 28–31.Google Scholar
  142. 142.
    RecordC.O., SkinnerJ.M., SleightP. and SpellerD.C.E. (1971): Candida endocarditis treated with 5-fluorocytosine - Br. Med. J. i: 262–264.Google Scholar
  143. 143.
    RobinsonM.F., Forgan-SmithW.R. and CraswellP.W. (1975): Candida thyroiditis — treated with 5-fluorocytosine- Aust. N.Z. J. Med. 5: 472–474.Google Scholar
  144. 144.
    RupprechtL., JanzenR. and VossH.V. (1974): Candidiasis bei immunsuppressiver Therapie in Kindesalter] - Monatsschr. Kinderheilkd. 122: 653–654.Google Scholar
  145. 145.
    RyleyJ.F., WilsonR.G. and Barret-BeeK.J. (1984): Azole resistance in Candida albicans - Sabouraudia 22: 53–63.Google Scholar
  146. 146.
    SafeL.M., SafeS.H., SubdenR.E. and MorrisD.C. (1977): Sterol content and polyene antibiotic resistance in isolates of Candida krusei, Candida parakrusei, and Candida tropicalis - Can. J. Microbiol. 23: 398–401.Google Scholar
  147. 147.
    SalkinI.F. and HurdN. (1972): Quantitative evaluation of the antifungal properties of cycloheximide - Antimicrob. Agents Chemother. 1: 177–184.Google Scholar
  148. 148.
    ScandellaD., RooneyR. and KatzE.R. (1980): Genetic, biochemical, and developmental studies of nystatin resistant mutant in Dictyostelium discoideum - Molec. Gen. Genet. 180: 67–75.Google Scholar
  149. 149.
    ScholerH.J. (1974): Experimental chemotherapy of aspergillosis. In: De Haller R. and Suter E. eds. Aspergillosis and Farmer's Lung in Man and Animal. Huber, Bern, pp. 136–147.Google Scholar
  150. 150.
    ScholerH.J. (1976): Grundlagen und Ergebnisse der antimykotischen Chemotherapie mit 5-Fluorocytosine- Chemotherapy (Basel) 22: 103–146.Google Scholar
  151. 151.
    ScholerH.J. (1980): Flucytosine. In: Speller D.C.E. ed. Antifungal Chemotherapy. John Wiley & Sons, New York, N.Y. pp. 35–106.Google Scholar
  152. 152.
    SchönebeckJ. and ÅnsêhnS. (1973): 5-Fluorocytosine resistance in Candida spp. and Torulopsis glabrata - Sabouraudia 11: 10–20.Google Scholar
  153. 153.
    SchröterG.P., TempleD.R., HusbergB.S., WeilR. and StarzlT.E. (1976): Cryptococcosis after renal transplantation; report of ten cases - Surgery 79: 268–277.Google Scholar
  154. 154.
    SegalE., RomanoA., EylanE. and SteinR. (1975): Experimental and clinical studies of 5-fluorocytosine activity in Candida ocular infections. I. In vitro activity of 5-fluorocytosine on Candida sp.- Chemotherapy (Basel) 21: 358–366.Google Scholar
  155. 155.
    ShadomyS. (1970): Further in vitro studies with 5-fluorocytosine- Infect. Immun. 2: 484–488.Google Scholar
  156. 156.
    ShadomyS., KirchhoffC.B. and IngroffA.E. (1973): In vitro activity of 5-fluorocytosine against Candida and Torulopsis species - Antimicrob. Agents Chemother. 3: 9–14.Google Scholar
  157. 157.
    ShadomyS., ShadomyH.J., McCayJ.A. and UtzJ.P. (1969): In vitro susceptibility studies with Cryptococcus neoformans and amphotericin B, hamycin and 5-fluorocytosine - Antimicrob. Agents Chemother. - 1968, American Society of Microbiology, Ann Arbor, pp. 452–460.Google Scholar
  158. 158.
    ShadomyS., WagnerG., Espinel-IngroffA. and DaviesB.A. (1975): In vitro studies with combinations of 5-fluorocytosine and arnphotericin B - Antimicrob. Agents Chemother. 8: 117–121.Google Scholar
  159. 159.
    SheldonG.M. and AlexanderR.L. (1974): Candida endophthalmitis - Can. J. Ophthalmol. 9: 146–149.Google Scholar
  160. 160.
    SmithK.J., WarnockD.W., KennedyC.T.C., JohnsonE.M., HopwoodV., VanCutsemJ, and Vanden BosscheH. (1986): Azole resistance in Candida albicans - J. Med. Vet. Mycol. 24: 133–144.Google Scholar
  161. 161.
    SnowR.M. and DismukesW.E. (1975): Cryptococcal meningitis - Arch. Intern. Med. 135: 1155–1157.Google Scholar
  162. 162.
    Sorensen L.J., McNall E.G. and Sternberg T.H. (1959): The development of strains of Candida albicans and Coccidioides immitis, which are resistant to amphotericin B — Antibiot. Ann. 1958–1959. pp. 920–923.Google Scholar
  163. 163.
    SpellerD.C.E. (1974): Torulopsis glabrata urinary tract infection treated with 5-fluorocytosine - J. Clin. Path. 27: 50–52.Google Scholar
  164. 164.
    SpellerD.C.E. and DaviesM.G. (1973): Sensitivity of yeasts to 5-fluorocytosine - J. Med. Microbiol. 6: 315–321.Google Scholar
  165. 165.
    SteerP., MarksM.J., KliteP.D. and EickhoffT.C. (1972): 5-fluorocytosine, an oral antifungal compound - Ann. Intern. Med. 76: 15–22.Google Scholar
  166. 166.
    StillerR.L., BennetJ.E., ScholerH.J., WallM., PolakA. and StevensD.A. (1982): Susceptibility to 5-fluorocytosine and prevalence of serotype in 402 Candida albicans isolates from the United States -Antimicrob. Agents Chemother. 22: 482–487.Google Scholar
  167. 167.
    StoneR.D., IrvineA.R. and O'ConnerG.R. (1975): Candida endophthalmitis: report of an unusual case with isolation of the etiologic agent by vitreous biopsy - Ann. Ophthalmol. 7: 757–762.Google Scholar
  168. 168.
    Stout H.A. and Pagano J.F. (1956): Resistance studies with nystatin – Antibiot. Ann. 1955–1956, pp. 704–710.Google Scholar
  169. 169.
    SugarmanB. and PesantiE. (1980): Treatment failure secondary to in vivo development of drug resistance by microorganisms - Rev. Infect. Dis. 2: 153–168.Google Scholar
  170. 170.
    TavitianA., RaufmanJ.-P., RosenthalL.E, WeberJ., WebberC.A. and DincsoyH.P. (1986): Ketoconazole-resistant Candida esophagitis in patients with acquied immunodeficiency syndrome -Gastroenterol. 90: 443–445.Google Scholar
  171. 171.
    TitsworthE. and GrunbergE. (1973): Chemotherapeutic activity of 5-fluorocytosine and amphotericin B against Candida albicans in mice -Antimicrob. Agents Chemother. 4: 306–308.Google Scholar
  172. 172.
    TuylJ.M. van (1975): Genetic aspects of acquired resistance to benomyl and thiabendazole in a number of fungi - Mel. Fac. Landbouww. Rijksuniv. Gent. 40: 691–697.Google Scholar
  173. 173.
    UrabeH., SuenagaY., YasudaM. and KodaH. (1977): Treatment of cutaneou candidiasis and chromomycosis with 5-fluorocytosine In: Iwata K. ed. Recent Advances in Medical and Veterinary Mycology. Proc. 6th International Congress of ISHAM, Tokyo, 1975, University of Tokyo Press, Tokyo, pp. 97–106.Google Scholar
  174. 174.
    UtzJ.P., GarriquesI.L., SandeM.A., WarnerJ.F., McGeheeR.F. and ShadomyS. (1975): Combined flucytosine-amphotericin B treatment of cryptococcal infections - J. Infect. Dis. 132: 368–373.Google Scholar
  175. 175.
    UtzJ.P. and ShadomyS. (1977): Antifungal activity of 5-fluorocytosine as measured by disk diffusion susceptibility testing - J. Infect. Dis. 135: 970–974.Google Scholar
  176. 176.
    VaughanS. (1977): The sensitivity of C. albicans to 5-fluorocytosine - N.Z.J. Med. Lab. Technol. 31:4–5.Google Scholar
  177. 177.
    WagnerG., ShadomyS., PaxtonL.D. and Espinel-IngroffA. (1975): New method for susceptibility testing with antifungal agents - Antimicrob. Agents Chemother. 8: 107–109.Google Scholar
  178. 178.
    WaitzJ.A., MossE.C. and WeinsteinM.J. (1971): Chemotherapeutic evaluation of clotrimazole. -Appl. Microbiol. 22: 891–894.Google Scholar
  179. 179.
    WarnocD.W., JohnsonG.M. and RichardsonM.D. (1983): Modified response to ketoconazole of Candida albicans from a treatment failure -Lancet i: 642–643.Google Scholar
  180. 180.
    WatsonP.E., RoseM.E. and KellyS.L. (1988): Isolation and analysis of ketoconazole resistant mutants of Saccharomyces cerevisiae - J. Med. Vet. Mycol. 26: 153–162.Google Scholar
  181. 181.
    WhelanW.L., BenekeE.S., RogersA.L. and SoilD.R. (1981): Segregation of 5-fluorocytosine-resistant variants by Candida albicans - Antimicrob. Agents Chemother. 19: 1078–1081.Google Scholar
  182. 182.
    WhelanW.L. and MageeP.T. (1981): Natural heterozygosity in Candida albicans - J. Bacteriol. 145: 896–903.Google Scholar
  183. 183.
    WhelanW.L., PatridgeR.M. and MageeP.T. (1980): Heterozygosity and segregation in Candida albicans- Molec. Gen. Genet. 180: 107–113.Google Scholar
  184. 184.
    WhiffenA.J. (1948): The production, assay and antibiotic activity of actidione, an antibiotic from Streptomyces griseus - J. Bacteriol. 56: 283–291.Google Scholar
  185. 185.
    WhitingD.A. (1967): Treatment of chromoblastomycosis with high local concentrations of amphotericin B - Br. J. Dermatol. 79: 345–351.Google Scholar
  186. 186.
    WilkieD. and LeeB.K. (1965): Genetic analysis of actidione resistance in Saccharomyces cerevisiae -Genet. Res. Camb. 6: 130–138.Google Scholar
  187. 187.
    WoodsR.A. (1971): Nystatin-resistant mutants of yeast; alterations in sterol content - J. Bacteriol. 108: 69–73.Google Scholar
  188. 188.
    WoodsR.A., BardM., JacksonI.E. and DrutzD.J. (1974): Resistance to polyene antibiotics and a correlated sterol changes in two isolates of Candida tropicalis from a patient with an amphotericin B-resistant funguria - J. Infect. Dis. 129: 53–58.Google Scholar
  189. 189.
    YamamotoM. (1980): Genetic analysis of resistant mutants to antimitotic benzimidazole compounds in Schizosaccharomyces pombe - Molec. Gen. Genet. 180: 231–234.Google Scholar
  190. 190.
    YangcoB.G., TeStrakeD. and OkaforJ. (1984): Phialophora richardsiae isolated from infected human bone - Mycopathol. 86: 103–111.Google Scholar
  191. 191.
    YoungC.N. (1972): Sensitivity patterns to griseofulvin of Trichophyton rubrum and other ringworm fungi - Trans a. Rep. St. John's Hosp. Derm. Soc. 58: 226–234.Google Scholar

Copyright information

© Gustav Fischer 1992

Authors and Affiliations

  • K. Iwata
    • 1
  1. 1.Department of Bacteriology - Faculty of MedicineUniversity of TokyoTokyoJapan

Personalised recommendations