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Resistance to Antifungal Drugs

  • Dominique Sanglard
Chapter

Abstract

Fungal infections caused by fungal pathogens are common in immunocompromised hosts. Candida spp. comprise the major yeast species recovered from infected individuals; however, other yeast species such as Cryptococcus neoformans might also be isolated. Among filamentous fungi causing infections in human, Aspergillus fumigatus has a dominant position, and this fungal species is linked to a high mortality [1]. Not only are a restricted number of antifungal agents available to treat these infections, but also resistance to antifungal treatment can occur. Table 1 summarizes the activity of known antifungal agents in several yeast species and A. fumigatus.

Keywords

Minimal Inhibitory Concentration Antifungal Agent Multidrug Transporter Azole Resistance Azole Antifungal Agent 
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.

References

  1. 1.
    Latge JP. Aspergillus fumigatus and aspergillosis. Clin Microbiol Rev. 1999;12:310–50.PubMedGoogle Scholar
  2. 2.
    Arikan S. Current status of antifungal susceptibility testing methods. Med Mycol. 2007;45:569–87.PubMedGoogle Scholar
  3. 3.
    Rex JH, Pfaller MA, Galgiani JN, et al. Development of interpretive breakpoints for antifungal susceptibility testing: Conceptual framework and analysis of in vitro-in vivo correlation data for fluconazole, itraconazole, and Candida infections. Subcommittee on Antifungal Susceptibility Testing of the National Committee for Clinical Laboratory Standards. Clin Infect Dis. 1997;24:235–47.PubMedGoogle Scholar
  4. 4.
    Cuesta I, Bielza C, Larranaga P, et al. Data mining validation of fluconazole breakpoints established by the European Committee on Antimicrobial Susceptibility Testing. Antimicrob Agents Chemother. 2009;53:2949–54.PubMedGoogle Scholar
  5. 5.
    EUCAST-AFST (European Committee on Antimicrobial Susceptibility Testing). EUCAST Technical Note on fluconazole. Clin Microbiol Infect. 2008;14:193–5.Google Scholar
  6. 6.
    EUCAST-AFST (European Committee on Antimicrobial Susceptibility Testing). EUCAST Technical Note on voriconazole. Clin Microbiol Infect. 2008;14:985–7.Google Scholar
  7. 7.
    Rex JH, Cooper Jr CR, Merz WG, Galgiani JN, Anaissie EJ. Detection of amphotericin B-resistant Candida isolates in a broth-based system. Antimicrob Agents Chemother. 1995;39:906–9.PubMedGoogle Scholar
  8. 8.
    Peyron F, Favel A, Michel-Nguyen A, Gilly M, Regli P, Bolmstrom A. Improved detection of amphotericin B-resistant isolates of Candida lusitaniae by Etest. J Clin Microbiol. 2001;39:339–42.PubMedGoogle Scholar
  9. 9.
    Pfaller MA, Messer SA, Hollis RJ. Strain delineation an antifungal susceptibilities of epidemiologically releated and unrelated isolates of Candida lusitaniae. Diagnostic Microbiology and Infectious Disease. 1994;20:127–33.PubMedGoogle Scholar
  10. 10.
    Walsh TJ, Melcher GP, Rinaldi MG, et al. Trichosporon beigelii, an emerging pathogen resistant to amphotericin B. J Clin Microbiol. 1990;28:1616–22.PubMedGoogle Scholar
  11. 11.
    Nolte FS, Parkinson T, Falconer DJ, et al. Isolation and characterization of fluconazole- and amphotericin B-resistant Candida albicans from blood of two patients with leukemia. Antimicrob Agents Chemother. 1997;44:196–9.Google Scholar
  12. 12.
    Chau AS, Gurnani M, Hawkinson R, Laverdiere M, Cacciapuoti A, McNicholas PM. Inactivation of sterol Delta5, 6-desaturase attenuates virulence in Candida albicans. Antimicrob Agents Chemother. 2005;49:3646–51.PubMedGoogle Scholar
  13. 13.
    Kelly SL, Lamb DC, Taylor M, Corran AJ, Baldwin BC, Powderly WG. Resistance to amphotericin B associated with defective sterol delta 8–7 isomerase in a Cryptococcus neoformans strain from an AIDS patient. FEMS Microbiol Lett. 1994;122:39–42.PubMedGoogle Scholar
  14. 14.
    Vandeputte P, Tronchin G, Berges T, Hennequin C, Chabasse D, Bouchara JP. Reduced susceptibility to polyenes associated with a missense mutation in the ERG6 gene in a clinical isolate of Candida glabrata with pseudohyphal growth. Antimicrob Agents Chemother. 2007;51:982–90.PubMedGoogle Scholar
  15. 15.
    Vandeputte P, Tronchin G, Larcher G, et al. A nonsense mutation in the ERG6 gene leads to reduced susceptibility to polyenes in a clinical isolate of Candida glabrata. Antimicrob Agents Chemother. 2008;52:3701–9.PubMedGoogle Scholar
  16. 16.
    Sanglard D, Ischer F, Parkinson T, Falconer D, Bille J. Candida albicans mutations in the ergosterol biosynthetic pathway and resistance to several antifungal agents. Antimicrob Agents Chemother. 2003;47:2404–12.PubMedGoogle Scholar
  17. 17.
    Dick JD, Merz WG, Saral R. Incidence of polyene-resistant yeasts recovered from clinical specimens. Antimicrob Agents Chemother. 1980;18:158–63.PubMedGoogle Scholar
  18. 18.
    Sokol-Anderson ML, Brajtburg J, Medoff G. Amphotericin B-induced oxidative damage and killing of Candida albicans. J Infect Dis. 1986;154:76–83.PubMedGoogle Scholar
  19. 19.
    Polak A. Mode of action studies. In: Ryley JF, editor. Chemotherapy of fungal Diseases. Berlin: Springer-Verlag; 1990. p. 153–82.Google Scholar
  20. 20.
    Coleman DC, Rinaldi MG, Haynes KA, et al. Importance of Candida species other than Candida albicans as opportunistic pathogens. Med Mycol. 1998;36:156–65.PubMedGoogle Scholar
  21. 21.
    Groll AH, Piscitelli SC, Walsh TJ. Clinical pharmacology of systemic antifungal agents: a comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Adv Pharmacol. 1998;44:343–500.PubMedGoogle Scholar
  22. 22.
    Vanden Bossche H, Marichal P, Odds FC. Molecular mechanisms of drug resistance in fungi. Trends in Microbiology. 1994;2:393–400.Google Scholar
  23. 23.
    Dodgson AR, Dodgson KJ, Pujol C, Pfaller MA, Soll DR. Clade-specific flucytosine resistance is due to a single nucleotide change in the FUR1 gene of Candida albicans. Antimicrob Agents Chemother. 2004;48:2223–7.PubMedGoogle Scholar
  24. 24.
    Hope WW, Tabernero L, Denning DW, Anderson MJ. Molecular mechanisms of primary resistance to flucytosine in Candida albicans. Antimicrob Agents Chemother. 2004;48:4377–86.PubMedGoogle Scholar
  25. 25.
    Smith WJ, Drew RH, Perfect JR. Posaconazole’s impact on prophylaxis and treatment of invasive fungal infections: an update. Expert Rev Anti Infect Ther. 2009;7:165–81.PubMedGoogle Scholar
  26. 26.
    Rex JH, Bennett JE, Sugar AM, et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute. N Engl J Med. 1994;331:1325–30.PubMedGoogle Scholar
  27. 27.
    White TC, Marr KA, Bowden RA. Clinical, cellular, and molecular factors that contribute to antifungal drug resistance. Clin Microbiol Rev. 1998;11:382–402.PubMedGoogle Scholar
  28. 28.
    Sanglard D, Bille J. Current understanding of the mode of action and of resistance mechanisms to conventional and emerging antifungal agents for treatment of Candida infections. In: Calderone R, editor. Candida and Candidiasis. Washington, DC: ASM press; 2002. p. 349–83.Google Scholar
  29. 29.
    Sanglard D, Kuchler K, Ischer F, Pagani JL, Monod M, Bille J. Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters. Antimicrob Agents Chemother. 1995;39:2378–86.PubMedGoogle Scholar
  30. 30.
    Sanglard D, Ischer F, Monod M, Bille J. Cloning of Candida albicans genes conferring resistance to azole antifungal agents: characterization of CDR2, a new multidrug ABC-transporter gene. Microbiology. 1997;143:405–16.PubMedGoogle Scholar
  31. 31.
    Moran GP, Sanglard D, Donnelly S, Shanley DB, Sullivan DJ, Coleman DC. Identification and expression of multidrug transporters responsible for fluconazole resistance in Candida dubliniensis. Antimicrob Agents Chemother. 1998;42:1819–30.PubMedGoogle Scholar
  32. 32.
    Perea S, Lopez-Ribot JL, Wickes BL, et al. Molecular mechanisms of fluconazole resistance in Candida dubliniensis isolates from human immunodeficiency virus-infected patients with oropharyngeal candidiasis. Antimicrob Agents Chemother. 2002;46:1695–703.PubMedGoogle Scholar
  33. 33.
    Barchiesi F, Calabrese D, Sanglard D, et al. Experimental induction of fluconazole resistance in Candida tropicalis ATCC 750. Antimicrob Agents Chemother. 2000;44:1578–84.PubMedGoogle Scholar
  34. 34.
    Sanglard D, Ischer F, Bille J. Role of ATP-binding-cassette transporter genes in high-frequency acquisition of resistance to azole antifungals in Candida glabrata. Antimicrob Agents Chemother. 2001;45:1174–83.PubMedGoogle Scholar
  35. 35.
    Sanglard D, Ischer F, Calabrese D, Majcherczyk PA, Bille J. The ATP binding cassette transporter gene CgCDR1 from Candida glabrata is involved in the resistance of clinical isolates to azole antifungal agents. Antimicrob Agents Chemother. 1999;43:2753–65.PubMedGoogle Scholar
  36. 36.
    Torelli R, Posteraro B, Ferrari S, et al. The ATP-binding cassette transporter–encoding gene CgSNQ2 is contributor to the CgPdr1-dependent azole resistance in Candida glabrata. Mol Microbiol. 2008;68:186–201.PubMedGoogle Scholar
  37. 37.
    Posteraro B, Sanguinetti M, Sanglard D, et al. Identification and characterization of a Cryptococcus neoformans ATP binding cassette (ABC) transporter-encoding gene, CnAFR1, involved in the resistance to fluconazole. Mol Microbiol. 2003;47:357–71.PubMedGoogle Scholar
  38. 38.
    Slaven JW, Anderson MJ, Sanglard D, et al. Induced expression of a novel Aspergillus fumigatus ABC transporter gene, atrF, in response to itraconazole. Fungal Genet Biol. 2002;36:199–206.PubMedGoogle Scholar
  39. 39.
    Nakamura K, Niimi M, Niimi K, et al. Functional expression of Candida albicans drug efflux pump Cdr1p in a Saccharomyces cerevisiae strain deficient in membrane transporters. Antimicrob Agents Chemother. 2001;45:3366–74.PubMedGoogle Scholar
  40. 40.
    Wirsching S, Michel S, Morschhauser J. Targeted gene disruption in Candida albicans wild-type strains: the role of the MDR1 gene in fluconazole resistance of clinical Candida albicans isolates. Mol Microbiol. 2000;36:856–65.PubMedGoogle Scholar
  41. 41.
    Wirsching S, Moran GP, Sullivan DJ, Coleman DC, Morschhauser J. MDR1-mediated drug resistance in Candida dubliniensis. Antimicrob Agents Chemother. 2001;45:3416–21.PubMedGoogle Scholar
  42. 42.
    Sanglard D, Ischer F, Monod M, Bille J. Susceptibilities of Candida albicans multidrug transporter mutants to various antifungal agents and other metabolic inhibitors. Antimicrob Agents Chemother. 1996;40:2300–5.PubMedGoogle Scholar
  43. 43.
    Marr KA, Lyons CN, Rustad TR, Bowden RA, White TC, Rustad T. Rapid, transient fluconazole resistance in Candida albicans is associated with increased mRNA levels of CDR. Antimicrob Agents Chemother. 1998;42:2584–9.PubMedGoogle Scholar
  44. 44.
    Marr KA, Lyons CN, Ha K, Rustad TR, White TC. Inducible azole resistance associated with a heterogeneous phenotype in Candida albicans. Antimicrob Agents Chemother. 2001;45:52–9.PubMedGoogle Scholar
  45. 45.
    Ferrari S, Ischer F, Calabrese D, et al. Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence. PLoS Pathog. 2009;5:e1000268.PubMedGoogle Scholar
  46. 46.
    Brun S, Berges T, Poupard P, et al. Mechanisms of azole resistance in petite mutants of Candida glabrata. Antimicrob Agents Chemother. 2004;48:1788–96.PubMedGoogle Scholar
  47. 47.
    De Micheli M, Bille J, Schueller C, Sanglard D. A common drug-responsive element mediates the upregulation of the Candida albicans ABC transporters CDR1 and CDR2, two genes involved in antifungal drug resistance. Mol Microbiol. 2002;43:1197–214.PubMedGoogle Scholar
  48. 48.
    Wirsching S, Michel S, Kohler G, Morschhauser J. Activation of the multiple drug resistance gene MDR1 in fluconazole- resistant, clinical Candida albicans strains is caused by mutations in a trans-regulatory factor. J Bacteriol. 2000;182:400–4.PubMedGoogle Scholar
  49. 49.
    Karnani N, Gaur NA, Jha S, et al. SRE1 and SRE2 are two specific steroid-responsive modules of Candida drug resistance gene 1 (CDR1) promoter. Yeast. 2004;21:219–39.PubMedGoogle Scholar
  50. 50.
    Gaur NA, Puri N, Karnani N, Mukhopadhyay G, Goswami SK, Prasad R. Identification of a negative regulatory element which regulates basal transcription of a multidrug resistance gene CDR1 of Candida albicans. FEMS Yeast Res. 2004;4:389–99.PubMedGoogle Scholar
  51. 51.
    Hikkel I, Lucau-Danila A, Delaveau T, Marc P, Devaux F, Jacq C. A general strategy to uncover transcription factor properties identifies a new regulator of drug resistance in yeast. J Biol Chem. 2003;278:11427–32.PubMedGoogle Scholar
  52. 52.
    Kren A, Mamnun YM, Bauer BE, et al. War1p, a novel transcription factor controlling weak acid stress response in yeast. Mol Cell Biol. 2003;23:1775–85.PubMedGoogle Scholar
  53. 53.
    Mendizabal I, Rios G, Mulet JM, Serrano R, de Larrinoa IF. Yeast putative transcription factors involved in salt tolerance. FEBS Lett. 1998;425:323–8.PubMedGoogle Scholar
  54. 54.
    Schjerling P, Holmberg S. Comparative amino acid sequence analysis of the C6 zinc cluster family of transcriptional regulators. Nucleic Acids Res. 1996;24:4599–607.PubMedGoogle Scholar
  55. 55.
    Rustad TR, Stevens DA, Pfaller MA, White TC. Homozygosity at the Candida albicans MTL locus associated with azole resistance. Microbiology. 2002;148:1061–72.PubMedGoogle Scholar
  56. 56.
    Coste AT, Karababa M, Ischer F, Bille J, Sanglard D. TAC1, Transcriptional activator of CDR genes, is a new transcription factor involved in the regulation of Candida albicans ABC transporters CDR1 and CDR2. Eukaryot Cell. 2004;3:1639–52.PubMedGoogle Scholar
  57. 57.
    Raad I, Chatzinikolaou I, Chaiban G, et al. In vitro and ex vivo activities of minocycline and EDTA against microorganisms embedded in biofilm on catheter surfaces. Antimicrob Agents Chemother. 2003;47:3580–5.PubMedGoogle Scholar
  58. 58.
    Riggle PJ, Kumamoto CA. Transcriptional regulation of MDR1, encoding a drug efflux determinant, in fluconazole-resistant Candida albicans strains through an Mcm1p binding site. Eukaryot Cell. 2006;5:1957–68.PubMedGoogle Scholar
  59. 59.
    Rognon B, Kozovska Z, Coste AT, Pardini G, Sanglard D. Identification of promoter elements responsible for the regulation of MDR1 from Candida albicans, a major facilitator transporter involved in azole resistance. Microbiology. 2006;152:3701–22.PubMedGoogle Scholar
  60. 60.
    Harry JB, Oliver BG, Song JL, et al. Drug-induced regulation of the MDR1 promoter in Candida albicans. Antimicrob Agents Chemother. 2005;49:2785–92.PubMedGoogle Scholar
  61. 61.
    Nguyen DT, Alarco AM, Raymond M. Multiple Yap1p-binding sites mediate induction of the yeast major facilitator FLR1 gene in response to drugs, oxidants, and alkylating agents. J Biol Chem. 2001;276:1138–45.PubMedGoogle Scholar
  62. 62.
    Morschhauser J, Barker KS, Liu TT, Bla BWJ, Homayouni R, Rogers PD. The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans. PLoS Pathog. 2007;3:e164.PubMedGoogle Scholar
  63. 63.
    Schubert S, Rogers PD, Morschhauser J. Gain-of-function mutations in the transcription factor MRR1 are responsible for overexpression of the MDR1 efflux pump in fluconazole-resistant Candida dubliniensis strains. Antimicrob Agents Chemother. 2008;52:4274–80.PubMedGoogle Scholar
  64. 64.
    Vermitsky JP, Edlind TD. Azole resistance in Candida glabrata: coordinate upregulation of multidrug transporters and evidence for a Pdr1-like transcription factor. Antimicrob Agents Chemother. 2004;48:3773–81.PubMedGoogle Scholar
  65. 65.
    Tsai HF, Krol AA, Sarti KE, Bennett JE. Candida glabrata PDR1, a transcriptional regulator of a pleiotropic drug resistance network, mediates azole resistance in clinical isolates and petite mutants. Antimicrob Agents Chemother. 2006;50:1384–92.PubMedGoogle Scholar
  66. 66.
    Vermitsky JP, Earhart KD, Smith WL, Homayouni R, Edlind TD, Rogers PD. Pdr1 regulates multidrug resistance in Candida glabrata: gene disruption and genome-wide expression studies. Mol Microbiol. 2006;61:704–22.PubMedGoogle Scholar
  67. 67.
    MacPherson S, Larochelle M, Turcotte B. A fungal family of transcriptional regulators: the zinc cluster proteins. Microbiol Mol Biol Rev. 2006;70:583–604.PubMedGoogle Scholar
  68. 68.
    Thakur JK, Arthanari H, Yang F, et al. A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature. 2008;452:604–9.PubMedGoogle Scholar
  69. 69.
    Marichal P, Koymans L, Willemsens S, et al. Contribution of mutations in the cytochrome P450 14α-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans. Microbiology. 1999;145:2701–13.PubMedGoogle Scholar
  70. 70.
    Asai K, Tsuchimori N, Okonogi K, Perfect JR, Gotoh O, Yoshida Y. Formation of azole-resistant Candida albicans by mutation of sterol 14α  −  demethylase P450. Antimicrob Agents Chemother. 1999;43:1163–9.PubMedGoogle Scholar
  71. 71.
    Kelly SL, Lamb DC, Kelly DE. Y132H substitution in Candida albicans sterol 14alpha-demethylase confers fluconazole resistance by preventing binding to haem. FEMS Microbiol Lett. 1999;180:171–5.PubMedGoogle Scholar
  72. 72.
    Kelly SL, Lamb DC, Loeffler J, Einsele H, Kelly DE. The G464S amino acid substitution in Candida albicans sterol 14alpha- demethylase causes fluconazole resistance in the clinic through reduced affinity. Biochem Biophys Res Commun. 1999;262:174–9.PubMedGoogle Scholar
  73. 73.
    Favre B, Didmon M, Ryder NS. Multiple amino acid substitutions in lanosterol 14α-demethylase contribute to azole resistance in Candida albicans. Microbiology. 1999;145:2715–25.PubMedGoogle Scholar
  74. 74.
    Sanglard D, Ischer F, Koymans L, Bille J. Amino acid substitutions in the cytochrome P450 lanosterol 14α-demethylase (CYP51A1) from azole-resistant Candida albicans clinical isolates contributing to the resistance to azole antifungal agents. Antimicrob Agents Chemother. 1998;42:241–53.PubMedGoogle Scholar
  75. 75.
    Lamb DC, Kelly DE, White TC, Kelly SL. The R467K amino acid substitution in Candida albicans sterol 14alpha- demethylase causes drug resistance through reduced affinity. Antimicrob Agents Chemother. 2000;44:63–7.PubMedGoogle Scholar
  76. 76.
    Kudo M, Ohi M, Aoyama Y, Nitahara Y, Chung SK, Yoshida Y. Effects of Y132H and F145L substitutions on the activity, azole resistance and spectral properties of Candida albicans sterol 14-demethylase P450 (CYP51): A live example showing the selection of altered P450 through interaction with environmental compounds. J Biochem (Tokyo). 2005;137:625–32.Google Scholar
  77. 77.
    Diaz-Guerra TM, Mellado E, Cuenca-Estrella M, Rodriguez-Tudela JL. A point mutation in the 14alpha-sterol demethylase gene Cyp51A contributes to itraconazole resistance in Aspergillus fumigatus. Antimicrob Agents Chemother. 2003;47:1120–4.PubMedGoogle Scholar
  78. 78.
    Mann PA, Parmegiani RM, Wei SQ, et al. Mutations in Aspergillus fumigatus resulting in reduced susceptibility to posaconazole appear to be restricted to a single amino acid in the cytochrome P450 14alpha-demethylase. Antimicrob Agents Chemother. 2003;47:577–81.PubMedGoogle Scholar
  79. 79.
    Garcia-Effron G, Dilger A, Alcazar-Fuoli L, Park S, Mellado E, Perlin DS. Rapid detection of triazole antifungal resistance in Aspergillus fumigatus. J Clin Microbiol. 2008;46:1200–6.PubMedGoogle Scholar
  80. 80.
    Mellado E, Garcia-Effron G, Alcazar-Fuoli L, et al. A new Aspergillus fumigatus resistance mechanism conferring in vitro cross-resistance to azole antifungals involves a combination of cyp51A alterations. Antimicrob Agents Chemother. 2007;51:1897–904.PubMedGoogle Scholar
  81. 81.
    Snelders E, van der Lee HA, Kuijpers J, et al. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLoS Med. 2008;5:e219.PubMedGoogle Scholar
  82. 82.
    Rodero L, Mellado E, Rodriguez AC, et al. G484S amino acid substitution in lanosterol 14-alpha demethylase (ERG11) is related to fluconazole resistance in a recurrent Cryptococcus neoformans clinical isolate. Antimicrob Agents Chemother. 2003;47:3653–6.PubMedGoogle Scholar
  83. 83.
    Sionov E, Chang YC, Garraffo HM, Kwon-Chung KJ. Heteroresistance to fluconazole in Cryptococcus neoformans is intrinsic and associated with virulence. Antimicrob Agents Chemother. 2009;53:2804–15.PubMedGoogle Scholar
  84. 84.
    Vandeputte P, Larcher G, Berges T, Renier G, Chabasse D, Bouchara JP. Mechanisms of azole resistance in a clinical isolate of Candida tropicalis. Antimicrob Agents Chemother. 2005;49:4608–15.PubMedGoogle Scholar
  85. 85.
    White TC. Increased mRNA levels of ERG16, CDR, and MDR1 correlate with increases in azole resistance in Candida albicans isolates from a patient infected with human immunodeficiency virus. Antimicrob Agents Chemother. 1997;41:1482–7.PubMedGoogle Scholar
  86. 86.
    Perea S, Lopez-Ribot JL, Kirkpatrick WR, et al. Prevalence of molecular mechanisms of resistance to azole antifungal agents in Candida albicans strains displaying high-level fluconazole resistance isolated from human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 2001;45:2676–84.PubMedGoogle Scholar
  87. 87.
    Marichal P, Vanden Bossche H, Odds FC, et al. Molecular biological characterization of an azole-resistant Candida glabrata isolate. Antimicrob Agents Chemother. 1997;41:2229–37.PubMedGoogle Scholar
  88. 88.
    Vik A, Rine J. Upc2p and Ecm22p, dual regulators of sterol biosynthesis in Saccharomyces cerevisiae. Mol Cell Biol. 2001;21:6395–405.PubMedGoogle Scholar
  89. 89.
    MacPherson S, Akache B, Weber S, De Deken X, Raymond M, Turcotte B. Candida albicans zinc cluster protein Upc2p confers resistance to antifungal drugs and is an activator of ergosterol biosynthetic genes. Antimicrob Agents Chemother. 2005;49:1745–52.PubMedGoogle Scholar
  90. 90.
    Silver PM, Oliver BG, White TC. Role of Candida albicans transcription factor Upc2p in drug resistance and sterol metabolism. Eukaryot Cell. 2004;3:1391–7.PubMedGoogle Scholar
  91. 91.
    Oliver BG, Song JL, Choiniere JH, White TC. cis-Acting Elements within the Candida albicans ERG11 Promoter Mediate the Azole Response through Transcription Factor Upc2p. Eukaryot Cell. 2007;6:2231–9.PubMedGoogle Scholar
  92. 92.
    Carvajal E, van den Hazel HB, Cybularz-Kolaczkowska A, Balzi E, Goffeau A. Molecular and phenotypic characterization of yeast PDR1 mutants that show hyperactive transcription of various ABC multidrug transporter genes. Mol Gen Genet. 1997;256:406–15.PubMedGoogle Scholar
  93. 93.
    Coste AT, Turner V, Ischer F, et al. A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at Chromosome 5 to mediate antifungal resistance in Candida albicans. Genetics. 2006;172:2139–56.PubMedGoogle Scholar
  94. 94.
    Dunkel N, Blass J, Rogers PD, Morschhauser J. Mutations in the multidrug resistance regulator MRR1, followed by loss of heterozygosity, are the main cause of MDR1 overexpression in fluconazole-resistant Candida albicans strains. Mol Microbiol. 2008;69:827–40.PubMedGoogle Scholar
  95. 95.
    Dunkel N, Liu TT, Barker KS, Homayouni R, Morschhäuser J, Rogers PD. A gain-of-function mutation in the transcription factor Upc2p causes upregulation of ergosterol biosynthesis genes and increased fluconazole resistance in a clinical Candida albicans isolate. Eukaryot Cell. 2008;7:1180–90.PubMedGoogle Scholar
  96. 96.
    Coste A, Crittin J, Bauser C, Rohde B, Sanglard D. Functional analysis of cis- and trans- acting elements of the Candida albicans CDR2 promoter with a novel promoter reporter system. Eukaryot Cell. 2009;8:1250–67.PubMedGoogle Scholar
  97. 97.
    Znaidi S, De Deken X, Weber S, Rigby T, Nantel A, Raymond M. The zinc cluster transcription factor Tac1p regulates PDR16 expression in Candida albicans. Mol Microbiol. 2007;66:440–52.PubMedGoogle Scholar
  98. 98.
    Chen CG, Yang YL, Shih HI, Su CL, Lo HJ. CaNdt80 is involved in drug resistance in Candida albicans by regulating CDR1. Antimicrob Agents Chemother. 2004;48:4505–12.PubMedGoogle Scholar
  99. 99.
    Crowley JH, Leak Jr FW, Shianna KV, Tove S, Parks LW. A mutation in a purported regulatory gene affects control of sterol uptake in Saccharomyces cerevisiae. J Bacteriol. 1998;180:4177–83.PubMedGoogle Scholar
  100. 100.
    Pinjon E, Moran GP, Jackson CJ, et al. Molecular mechanisms of itraconazole resistance in Candida dubliniensis. Antimicrob Agents Chemother. 2003;47:2424–37.PubMedGoogle Scholar
  101. 101.
    Miyazaki Y, Geber A, Miyazaki H, et al. Cloning, sequencing, expression and allelic sequence diversity of ERG3 (C-5 sterol desaturase gene) in Candida albicans. Gene. 1999;236:43–51.PubMedGoogle Scholar
  102. 102.
    Coste A, Selmecki A, Forche A, et al. Genotypic evolution of azole resistance mechanisms in sequential Candida albicans isolates. Eukaryot Cell. 2007;6:1889–904.PubMedGoogle Scholar
  103. 103.
    Selmecki A, Forche A, Berman J. Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science. 2006;313:367–70.PubMedGoogle Scholar
  104. 104.
    Polakova S, Blume C, Zarate JA, et al. Formation of new chromosomes as a virulence mechanism in yeast Candida glabrata. Proc Natl Acad Sci U S A. 2009;106:2688–93.PubMedGoogle Scholar
  105. 105.
    Ramage G, Bachmann S, Patterson TF, Wickes BL, Lopez-Ribot JL. Investigation of multidrug efflux pumps in relation to fluconazole resistance in Candida albicans biofilms. J Antimicrob Chemother. 2002;49:973–80.PubMedGoogle Scholar
  106. 106.
    LaFleur MD, Kumamoto CA, Lewis K. Candida albicans biofilms produce antifungal-tolerant persister cells. Antimicrob Agents Chemother. 2006;50:3839–46.PubMedGoogle Scholar
  107. 107.
    Lewis K. Persister cells, dormancy and infectious disease. Nat Rev Microbiol. 2007;5:48–56.PubMedGoogle Scholar
  108. 108.
    Mukherjee PK, Chandra J, Kuhn DM, Ghannoum MA. Mechanism of fluconazole resistance in Candida albicans biofilms: phase-specific role of efflux pumps and membrane sterols. Infect Immun. 2003;71:4333–40.PubMedGoogle Scholar
  109. 109.
    Borecka-Melkusova S, Moran GP, Sullivan DJ, Kucharikova S, Chorvat Jr D, Bujdakova H. The expression of genes involved in the ergosterol biosynthesis pathway in Candida albicans and Candida dubliniensis biofilms exposed to fluconazole. Mycoses. 2009;52:118–28.PubMedGoogle Scholar
  110. 110.
    Cao YY, Cao YB, Xu Z, et al. cDNA microarray analysis of differential gene expression in Candida albicans biofilm exposed to farnesol. Antimicrob Agents Chemother. 2005;49:584–9.PubMedGoogle Scholar
  111. 111.
    Nett J, Lincoln L, Marchillo K, et al. Putative role of beta-1, 3 glucans in Candida albicans biofilm resistance. Antimicrob Agents Chemother. 2007;51:510–20.PubMedGoogle Scholar
  112. 112.
    Kurtz MB, Douglas CM. Lipopeptide inhibitors of fungal glucan synthase. J Med Vet Mycol. 1997;35:79–86.PubMedGoogle Scholar
  113. 113.
    Mio T, Adachi-Shimizu M, Tachibana Y, et al. Cloning of the Candida albicans homolog of Saccharomyces cerevisiae GSC1/FKS1 and its involvement in beta-1, 3-glucan synthesis. J Bacteriol. 1997;179:4096–105.PubMedGoogle Scholar
  114. 114.
    Pereira M, Felipe MS, Brigido MM, Soares CM, Azevedo MO. Molecular cloning and characterization of a glucan synthase gene from the human pathogenic fungus Paracoccidioides brasiliensis. Yeast. 2000;16:451–62.PubMedGoogle Scholar
  115. 115.
    Douglas CM, D’Ippolito JA, Shei GJ, et al. Identification of the FKS1 gene of Candida albicans as the essential target of 1, 3-beta-D-glucan synthase inhibitors. Antimicrob Agents Chemother. 1997;41:2471–9.PubMedGoogle Scholar
  116. 116.
    Thompson JR, Douglas CM, Li W, et al. A glucan synthase FKS1 homolog in Cryptococcus neoformans is single copy and encodes an essential function. J Bacteriol. 1999;181:444–53.PubMedGoogle Scholar
  117. 117.
    Onishi J, Meinz M, Thompson J, et al. Discovery of novel antifungal (1, 3)-beta-D-glucan synthase inhibitors. Antimicrob Agents Chemother. 2000;44:368–77.PubMedGoogle Scholar
  118. 118.
    Bowman JC, Hicks PS, Kurtz MB, et al. The antifungal echinocandin caspofungin acetate kills growing cells of Aspergillus fumigatus in vitro. Antimicrob Agents Chemother. 2002;46:3001–12.PubMedGoogle Scholar
  119. 119.
    Arikan S, Lozano-Chiu M, Paetznick V, Rex JH. In vitro susceptibility testing methods for caspofungin against Aspergillus and Fusarium isolates. Antimicrob Agents Chemother. 2001;45:327–30.PubMedGoogle Scholar
  120. 120.
    Douglas CM, Marrinan JA, Li W, Kurtz MB. A Saccharomyces cerevisiae mutant with echinocandin-resistant 1, 3-beta- D-glucan synthase. J Bacteriol. 1994;176:5686–96.PubMedGoogle Scholar
  121. 121.
    Frost DJ, Knapp M, Brandt K, Shadron A, Goldman RC. Characterization of a lipopeptide-resistant strain of Candida albicans. Can J Microbiol. 1997;43:122–8.PubMedGoogle Scholar
  122. 122.
    Park S, Kelly R, Kahn JN, et al. Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob Agents Chemother. 2005;49:3264–73.PubMedGoogle Scholar
  123. 123.
    Perlin DS. Resistance to echinocandin-class antifungal drugs. Drug Resist Updates. 2007;10:121–30.Google Scholar
  124. 124.
    Garcia-Effron G, Kontoyiannis DP, Lewis RE, Perlin DS. Caspofungin-resistant Candida tropicalis strains causing breakthrough fungemia in patients at high risk for hematologic malignancies. Antimicrob Agents Chemother. 2008;52:4181–3.PubMedGoogle Scholar
  125. 125.
    Cleary JD, Garcia-Effron G, Chapman SW, Perlin DS. Reduced Candida glabrata susceptibility secondary to an FKS1 mutation developed during candidemia treatment. Antimicrob Agents Chemother. 2008;52:2263–5.PubMedGoogle Scholar
  126. 126.
    Rocha EM, Garcia-Effron G, Park S, Perlin DS. A Ser678Pro substitution in Fks1p confers resistance to echinocandin drugs in Aspergillus fumigatus. Antimicrob Agents Chemother. 2007;51:4174–6.PubMedGoogle Scholar
  127. 127.
    Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS. A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility. Antimicrob Agents Chemother. 2008;52:2305–12.PubMedGoogle Scholar
  128. 128.
    Thompson GR, Wiederhold NP, Vallor AC, Villareal NC, Lewis JS, Patterson TF. Development of caspofungin resistance following prolonged therapy for invasive candidiasis secondary to Candida glabrata infection. Antimicrob Agents Chemother. 2008;52:3783–5.PubMedGoogle Scholar
  129. 129.
    Katiyar S, Pfaller M, Edlind T. Candida albicans and Candida glabrata clinical isolates exhibiting reduced echinocandin susceptibility. Antimicrob Agents Chemother. 2006;50:2892–4.PubMedGoogle Scholar
  130. 130.
    Reinoso-Martin C, Schuller C, Schuetzer-Muehlbauer M, Kuchler K. The yeast protein kinase C cell integrity pathway mediates tolerance to the antifungal drug caspofungin through activation of Slt2p mitogen-activated protein kinase signaling. Eukaryot Cell. 2003;2:1200–10.PubMedGoogle Scholar
  131. 131.
    Arendrup MC, Perkhofer S, Howard SJ, et al. Establishing in vitro-in vivo correlations for Aspergillus fumigatus: The challenge of azoles versus echinocandins. Antimicrob Agents Chemother. 2008;52:3504–11.PubMedGoogle Scholar
  132. 132.
    Martins MD, Lozano-Chiu M, Rex JH. Declining rates of oropharyngeal candidiasis and carriage of Candida albicans associated with trends toward reduced rates of carriage of fluconazole-resistant C. albicans in human immunodeficiency virus-infected patients. Clin Infect Dis. 1998;27:1291–4.PubMedGoogle Scholar
  133. 133.
    Sobel JD, Ohmit SE, Schuman P, et al. The evolution of Candida species and fluconazole susceptibility among oral and vaginal isolates recovered from human immunodeficiency virus (HIV)-seropositive and at-risk HIV-seronegative women. J Infect Dis. 2000;183:286–93.PubMedGoogle Scholar
  134. 134.
    Shahid Z, Sobel JD. Reduced fluconazole susceptibility of Candida albicans isolates in women with recurrent vulvovaginal candidiasis: Effects of long-term fluconazole therapy. Diagn Microbiol Infect Dis. 2009;64:354–6.PubMedGoogle Scholar
  135. 135.
    Bulik CC, Sobel JD, Nailor MD. Susceptibility profile of vaginal isolates of Candida albicans prior to and following fluconazole introduction – impact of two decades. Mycoses 2009. Epub ahead of print.Google Scholar
  136. 136.
    Sanglard D, Odds FC. Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences. Lancet Infect Dis. 2002;2:73–85.PubMedGoogle Scholar
  137. 137.
    Lass-Florl C. The changing face of epidemiology of invasive fungal disease in Europe. Mycoses. 2009;52:197–205.PubMedGoogle Scholar
  138. 138.
    Howard SJ, Cerar D, Anderson MJ, et al. Frequency and evolution of Azole resistance in Aspergillus fumigatus associated with treatment failure. Emerg Infect Dis. 2009;15:1068–76.PubMedGoogle Scholar
  139. 139.
    Brandt ME, Pfaller MA, Hajjeh RA, et al. Trends in antifungal drug susceptibility of Cryptococcus neoformans isolates in the United States: 1992 to 1994 and 1996 to 1998. Antimicrob Agents Chemother. 2001;45:3065–9.PubMedGoogle Scholar
  140. 140.
    Gehrt A, Peter J, Pizzo PA, Walsh TJ. Effect of increasing inoculum sizes of pathogenic filamentous fungi on MICs of antifungal agents by broth microdilution method. J Clin Microbiol. 1995;33:1302–7.PubMedGoogle Scholar
  141. 141.
    Pfaller MA, Messer SA, Hollis RJ, et al. Trends in species distribution and susceptibility to fluconazole among blood stream isolates of Candida species in the United States. Diagn Microbiol Infect Dis. 1999;33:217–22.PubMedGoogle Scholar
  142. 142.
    Pfaller MA, Messer SA, Hollis RJ, et al. In vitro susceptibilities of Candida bloodstream isolates to the new triazole antifungal agents BMS-207147, SCH 56592, and voriconazole. Antimicrob Agents Chemother. 1998;42:3242–4.PubMedGoogle Scholar
  143. 143.
    Yildiran ST, Saracli MA, Fothergill AW, Rinaldi MG. In vitro susceptibility of environmental Cryptococcus neoformans variety neoformans isolates from Turkey to six antifungal agents, including SCH56592 and voriconazole. Eur J Clin Microbiol Infect Dis. 2000;19:317–9.PubMedGoogle Scholar
  144. 144.
    Yamazumi T, Pfaller MA, Messer SA, Houston A, Hollis RJ, Jones RN. In vitro activities of ravuconazole (BMS-207147) against 541 clinical isolates of Cryptococcus neoformans. Antimicrob Agents Chemother. 2000;44:2883–6.PubMedGoogle Scholar
  145. 145.
    Uchida K, Yokota N, Yamaguchi H. In vitro antifungal activity of posaconazole against various pathogenic fungi. Int J Antimicrob Agents. 2001;18:167–72.PubMedGoogle Scholar
  146. 146.
    Mosquera J, Denning DW. Azole cross-resistance in Aspergillus fumigatus. Antimicrob Agents Chemother. 2002;46:556–7.PubMedGoogle Scholar
  147. 147.
    Bartizal K, Gill CJ, Abruzzo GK, et al. In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743, 872). Antimicrob Agents Chemother. 1997;41:2326–32.PubMedGoogle Scholar
  148. 148.
    Mikamo H, Sato Y, Tamaya T. In vitro antifungal activity of FK463, a new water-soluble echinocandin- like lipopeptide. J Antimicrob Chemother. 2000;46:485–7.PubMedGoogle Scholar
  149. 149.
    Chavez M, Bernal S, Valverde A, Gutierrez MJ, Quindos G, Mazuelos EM. In-vitro activity of voriconazole (UK-109,496), LY303366 and other antifungal agents against oral Candida spp. isolates from HIV-infected patients. J Antimicrob Chemother. 1999;44:697–700.PubMedGoogle Scholar
  150. 150.
    Pfaller MA, Messer SA, Coffman S. In vitro susceptibilities of clinical yeast isolates to a new echinocandin derivative, LY303366, and other antifungal agents. Antimicrob Agents Chemother. 1997;41:763–6.PubMedGoogle Scholar
  151. 151.
    Tawara S, Ikeda F, Maki K, et al. In vitro activities of a new lipopeptide antifungal agent, FK463, against a variety of clinically important fungi. Antimicrob Agents Chemother. 2000;44:57–62.PubMedGoogle Scholar
  152. 152.
    Espinel-Ingroff A. Comparison of In vitro activities of the new triazole SCH56592 and the echinocandins MK-0991 (L-743, 872) and LY303366 against opportunistic filamentous and dimorphic fungi and yeasts. J Clin Microbiol. 1998;36:2950–6.PubMedGoogle Scholar
  153. 153.
    Espinel-Ingroff A. In vitro antifungal activities of anidulafungin and micafungin, licensed agents and the investigational triazole posaconazole as determined by NCCLS methods for 12, 052 fungal isolates: review of the literature. Rev Iberoam Micol. 2003;20:121–36.PubMedGoogle Scholar
  154. 154.
    Arikan S, Yurdakul P, Hascelik G. Comparison of two methods and three end points in determination of in vitro activity of micafungin against Aspergillus spp. Antimicrob Agents Chemother. 2003;47:2640–3.PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Institute of MicrobiologyUniversity of Lausanne and University Hospital CenterLausanneSwitzerland

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