Current Fungal Infection Reports

, Volume 6, Issue 3, pp 154–164 | Cite as

Candida glabrata: Multidrug Resistance and Increased Virulence in a Major Opportunistic Fungal Pathogen

  • Michael A. Pfaller
  • Mariana Castanheira
  • Shawn R. Lockhart
  • Ronald N. Jones
Clinical Lab Issues (M Pfaller, Section Editor)


C. glabrata is widely acknowledged to be an important and potentially antifungal resistant cause of invasive candidiasis (IC). In the United States (US) both the frequency of C. glabrata as a cause of IC and in vitro resistance to fluconazole has increased steadily since 1992. Although this species is generally considered to be less virulent than C. albicans, recent findings suggest that gain of function (GOF) mutations in the transcriptional regulator CgPdr1p results not only in broad resistance to azole antifungals but also an increase in both fitness and virulence in animal models. Furthermore, case reports and case series suggest the emergence of multidrug resistance (MDR) in this species. Recent data from multicenter surveys conducted in the US have demonstrated the emergence of co-resistance to both azoles and echinocandins in clinical isolates of C. glabrata. These findings are highlighted in an effort to bring attention to this important development.


C. glabrata Multidrug resistance Virulence Hematogenously disseminated candidiasis (HDC) Invasive candidiasis (IC) 


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Alexander BD, Schell WA, Miller JL, Long GD, Perfect JR. Candida glabrata fungemia in transplant patients receiving voriconazole after fluconazole. Transplantation. 2005;80:868–71.PubMedCrossRefGoogle Scholar
  2. 2.
    Arendrup MC, Bruun B, Christensen JJ, et al. National surveillance of fungemia in Denmark (2004 to 2009). J Clin Microbiol. 2011;49:325–34.PubMedCrossRefGoogle Scholar
  3. 3.
    • Chapeland-Leclerc F, Hennequin C, Papon N, et al. Acquisition of flucytosine, azole, and caspofungin resistance in Candida glabrata bloodstream isolates serially obtained from a hematopoietic stem cell transplant recipient. Antimicrob Agents Chemother. 2010; 54:1360-1362. A remarkable case report that illustrates the ability of C. glabrata to assimilate multiple resistance mutations to antifungal agents.Google Scholar
  4. 4.
    Cohen Y, Karoubi P, Adrie C, et al. Early prediction of Candida glabrata fungemia in nonneutropenic critically ill patients. Crit Care Med. 2010;38:826–30.PubMedCrossRefGoogle Scholar
  5. 5.
    • Dannaoui E, Desnos-Ollivier M, Garcia-Hermoso D, et al. Candida spp. with acquired echinocandin resistance, France, 2004-2010. Emerg Infect Dis. 2012; 18:86-90. An important report concerning the emergence of echinocandin resistance in France. Google Scholar
  6. 6.
    Falagas ME, Roussos N, Vardakas KZ. Relative frequency of albicans and the various non-albicans Candida spp among candidemia isolates from inpatients in various parts of the world: a systematic review. Int J Infect Dis. 2010;14:e954–66.PubMedCrossRefGoogle Scholar
  7. 7.
    Fournier P, Schwebel C, Maubon D, et al. Antifungal use influences Candida species distribution and susceptibility in the intensive care unit. J Antimicrob Chemother. 2011;66:2880–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Klevay MJ, Ernst EJ, Hollanbaugh JL, Miller JG, Pfaller MA, Diekema DJ. Therapy and outcome of Candida glabrata versus Candida albicans bloodstream infection. Diagn Microbiol Infect Dis. 2008;60:273–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Klevay MJ, Horn DL, Neofytos D, Pfaller MA, Diekema DJ. Initial treatment and outcome of Candida glabrata versus Candida albicans bloodstream infection. Diagn Microbiol Infect Dis. 2009;64:152–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Krogh-Madsen M, Arendrup MC, Heslet L, Knudsen JD. Amphotericin B and caspofungin resistance in Candida glabrata isolates recovered from a critically ill patient. Clin Infect Dis. 2006;42:938–44.PubMedCrossRefGoogle Scholar
  11. 11.
    Lee I, Morales KH, Zaoutis TE, Fishman NO, Nachamkin I, Lautenbach E. Clinical and economic outcomes of decreased fluconazole susceptibility in patients with Candida glabrata bloodstream infections. Am J Infect Control. 2010;38:740–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Lee I, Zaoutis TE, Fishman NO, Morales KH, Nachamkin I, Lautenbach E. Risk factors for fluconazole resistance in patients with Candida glabrata bloodstream infection: potential impact of control group selection on characterizing the association between previous fluconazole use and fluconazole resistance. Am J Infect Control. 2010;38:456–60.PubMedCrossRefGoogle Scholar
  13. 13.
    • Lortholary O, Desnos-Ollivier M, Sitbon K, Fontanet A, Bretagne S, Dromer F. Recent exposure to caspofungin or fluconazole influences the epidemiology of candidemia: a prospective multicenter study involving 2,441 patients. Antimicrob Agents Chemother. 2011; 55:532-538. Another report from France that illustrates the fact that prior exposure to both fluconazole and caspofungin affects both species distribution and antifungal susceptibility.Google Scholar
  14. 14.
    Malani AN, Psarros G, Malani PN, Kauffman CA. Is age a risk factor for Candida glabrata colonisation? Mycoses. 2011;54:531–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Moran C, Grussemeyer CA, Spalding JR, Benjamin Jr DK, Reed SD. Comparison of costs, length of stay, and mortality associated with Candida glabrata and Candida albicans bloodstream infections. Am J Infect Control. 2010;38:78–80.PubMedCrossRefGoogle Scholar
  16. 16.
    Pfaller MA, Messer SA, Hollis RJ, et al. Variation in susceptibility of bloodstream isolates of Candida glabrata to fluconazole according to patient age and geographic location in the United States in 2001 to 2007. J Clin Microbiol. 2009;47:3185–90.PubMedCrossRefGoogle Scholar
  17. 17.
    Pfaller MA, Castanheira M, Messer SA, Moet GJ, Jones RN. Variation in Candida spp. distribution and antifungal resistance rates among bloodstream infection isolates by patient age: Report from the SENTRY Antimicrobial Surveillance Program (2008-2009). Diagn Microbiol Infect Dis. 2010;68:278–83.PubMedCrossRefGoogle Scholar
  18. 18.
    Pfaller MA, Diekema DJ, Gibbs DL, et al. Geographic variation in the frequency of isolation and fluconazole and voriconazole susceptibilities of Candida glabrata: An assessment from the ARTEMIS DISK Global Antifungal Surveillance Program. Diagn Microbiol Infect Dis. 2010;67:162–71.PubMedCrossRefGoogle Scholar
  19. 19.
    • Pfaller MA, Castanheira M, Lockhart SR, Ahlquist AM, Messer SA, Jones RN. Frequency of decreased susceptibility and resistance to echinocandins among fluconazole-resistant bloodstream isolates of Candida glabrata. J Clin Microbiol. 2012; 50:1199-1203. The first report of the emergence of co-resistance to fluconazole and the echinocandins in C. glabrata isolates from the US.Google Scholar
  20. 20.
    Pfeiffer CD, Garcia-Effron G, Zaas AK, Perfect JR, Perlin DS, Alexander BD. Breakthrough invasive candidiasis in patients on micafungin. J Clin Microbiol. 2010;48:2373–80.PubMedCrossRefGoogle Scholar
  21. 21.
    Sobel JD. Changing epidemiology of invasive candidiasis in intensive care units–much ado about nothing? Crit Care Med. 2008;36:2188–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Sobel JD. Changing trends in the epidemiology of Candida blood stream infections: A matter for concern? Crit Care Med. 2010;38:990–2.PubMedCrossRefGoogle Scholar
  23. 23.
    • Zimbeck AJ, Iqbal N, Ahlquist AM, et al. FKS mutations and elevated echinocandin MIC values among Candida glabrata isolates from U.S. population-based surveillance. Antimicrob Agents Chemother. 2010; 54:5042-2047. A report concerning echinocandin resistance in C. glabrata isolates from a US population-based survey.Google Scholar
  24. 24.
    Pappas PG, Rex JH, Sobel JD, et al. Guidelines for treatment of candidiasis. Clin Infect Dis. 2004;38:161–89.PubMedCrossRefGoogle Scholar
  25. 25.
    Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:503–35.PubMedCrossRefGoogle Scholar
  26. 26.
    Trick WE, Fridkin SK, Edwards JR, Hajjeh RA, Gaynes RP. Secular trend of hospital-acquired candidemia among intensive care unit patients in the United States during 1989-1999. Clin Infect Dis. 2002;35:627–30.PubMedCrossRefGoogle Scholar
  27. 27.
    Ahlquist A, Farley MM, Harrison LH, et al. Epidemiology of candidemia in metropolitan Atlanta and Baltimore City and County: Prelilminary results of population-based active, laboratory surveillance - 2008-2009. In: 49th ICAAC, September 12-15, 2009. San Francisco, California, USA: Antimicrob. Agents Chemother. 2009;Abstr. M-1241.Google Scholar
  28. 28.
    Pakyz AL, Gurgle HE, Oinonen MJ. Antifungal use in hospitalized adults in U.S. academic health centers. Am J Health Syst Pharm. 2011;68:415–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Hachem R, Hanna H, Kontoyiannis D, Jiang Y, Raad I. The changing epidemiology of invasive candidiasis: Candida glabrata and Candida krusei as the leading causes of candidemia in hematologic malignancy. Cancer. 2008;112:2493–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Hajjeh RA, Sofair AN, Harrison LH, et al. Incidence of bloodstream infections due to Candida species and in vitro susceptibilities of isolates collected from 1998 to 2000 in a population-based active surveillance program. J Clin Microbiol. 2004;42:1519–27.PubMedCrossRefGoogle Scholar
  31. 31.
    Pfaller MA, Diekema DJ. The epidemiology of invasive candidasis. RA Calderone and CJ Clancy (ed), Candida and Candidiasis, 2nd ed. Washington, D.C. USA: American Society for Microbiology. 2012; 449-480.Google Scholar
  32. 32.
    Sobel JD. The emergence of non-albicans Candida species as causes of invasive candidiasis and candidemia. Curr Infect Dis Rep. 2006;8:427–33.PubMedCrossRefGoogle Scholar
  33. 33.
    Chow JK, Golan Y, Ruthazer R, et al. Factors associated with candidemia caused by non-albicans Candida species versus Candida albicans in the intensive care unit. Clin Infect Dis. 2008;46:1206–13.PubMedCrossRefGoogle Scholar
  34. 34.
    Garey KW, Pai MP, Suda KJ, et al. Inadequacy of fluconazole dosing in patients with candidemia based on Infectious Diseases Society of America (IDSA) guidelines. Pharmacoepidemiol Drug Saf. 2007;16:919–27.PubMedCrossRefGoogle Scholar
  35. 35.
    Horn DL, Neofytos D, Anaissie EJ, et al. Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry. Clin Infect Dis. 2009;48:1695–703.PubMedCrossRefGoogle Scholar
  36. 36.
    Pasqualotto AC, Zimerman RA, Alves SH, et al. Take control over your fluconazole prescriptions: the growing importance of Candida glabrata as an agent of candidemia in Brazil. Infect Control Hosp Epidemiol. 2008;29:898–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Sendid B, Cotteau A, Francois N, et al. Candidaemia and antifungal therapy in a French University Hospital: Rough trends over a decade and possible links. BMC Infect Dis. 2006;6:80.PubMedCrossRefGoogle Scholar
  38. 38.
    Borst A, Raimer MT, Warnock DW, Morrison CJ, Arthington-Skaggs BA. Rapid acquisition of stable azole resistance by Candida glabrata isolates obtained before the clinical introduction of fluconazole. Antimicrob Agents Chemother. 2005;49:783–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Dery M, Hasbun R. Fluconazole-resistant Candida: Mechanisms and risk factor identification. Curr Fungal Infect Rep. 2011;5:23–8.CrossRefGoogle Scholar
  40. 40.
    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.Google Scholar
  41. 41.
    Pfaller MA, Diekema DJ. Azole antifungal drug cross-resistance: Mechanisms epidemiology, and clinical significance. J Invasive Fungal Infect. 2007;1:74–92.Google Scholar
  42. 42.
    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
  43. 43.
    Sanguinetti M, Posteraro B, Fiori B, Ranno S, Torelli R, Fadda G. Mechanisms of azole resistance in clinical isolates of Candida glabrata collected during a hospital survey of antifungal resistance. Antimicrob Agents Chemother. 2005;49:668–79.PubMedCrossRefGoogle Scholar
  44. 44.
    Betts RF, Nucci M, Talwar D, et al. A Multicenter, double-blind trial of a high-dose caspofungin treatment regimen versus a standard caspofungin treatment regimen for adult patients with invasive candidiasis. Clin Infect Dis. 2009;48:1676–84.PubMedCrossRefGoogle Scholar
  45. 45.
    Kuse ER, Chetchotisakd P, da Cunha CA, et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: A phase III randomised double-blind trial. Lancet. 2007;369:1519–27.PubMedCrossRefGoogle Scholar
  46. 46.
    Mora-Duarte J, Betts R, Rotstein C, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med. 2002;347:2020–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Pappas PG, Rotstein CM, Betts RF, et al. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis. 2007;45:883–93.PubMedCrossRefGoogle Scholar
  48. 48.
    Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med. 2007;356:2472–82.PubMedCrossRefGoogle Scholar
  49. 49.
    Shorr AF, Wu C, Kothari S. Outcomes with micafungin in patients with candidaemia or invasive candidiasis due to Candida glabrata and Candida krusei. J Antimicrob Chemother. 2011;66:375–80.PubMedCrossRefGoogle Scholar
  50. 50.
    Messer SA, Jones RN, Fritsche TR. International surveillance of Candida spp. and Aspergillus spp.: report from the SENTRY Antimicrobial Surveillance Program (2003). J Clin Microbiol. 2006;44:1782–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Pfaller MA, Boyken L, Hollis RJ, Messer SA, Tendolkar S, Diekema DJ. In vitro activities of anidulafungin against more than 2,500 clinical isolates of Candida spp., including 315 isolates resistant to fluconazole. J Clin Microbiol. 2005;43:5425–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Pfaller M, Boyken L, Hollis R, et al. Use of epidemiological cutoff values to examine 9-year trends in susceptibility of Candida species to anidulafungin, caspofungin, and micafungin. J Clin Microbiol. 2011;49:624–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Castanheira M, Woosley LN, Pfaller MA, Diekema DJ, Messer SA, Jones RN. Low prevalence of fks1 hotspot 1 mutations in a worldwide collection of Candida spp. Antimicrob Agents Chemother. 2010;54:2655–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Kofteridis DP, Lewis RE, Kontoyiannis DP. Caspofungin-non-susceptible Candida isolates in cancer patients. J Antimicrob Chemother. 2010;65:293–5.PubMedCrossRefGoogle Scholar
  55. 55.
    • Perlin DS. Echinocandin-resistant Candida: Molecular methods and phenotypes. Curr Fungal Infect Reports. 2011:5:113-119. A very well written review of aspects of echinocandin resistance in Candida.Google Scholar
  56. 56.
    Sanguinetti M, Posteraro P, Posteraro B. Echinocandin antifungal drug resistance in Candida species: a cause for concern? Curr Infect Dis Rep. 2010;12:437–43.PubMedCrossRefGoogle Scholar
  57. 57.
    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.PubMedCrossRefGoogle Scholar
  58. 58.
    Costa-de-Oliveira S. Marcos Miranda I, Silva RM, et al. FKS2 mutations associated with decreased echinocandin susceptibility of Candida glabrata following anidulafungin therapy. Antimicrob Agents Chemother. 2011;55:1312–4.PubMedCrossRefGoogle Scholar
  59. 59.
    Daneman N, Chan AK, Poutanen SM, Rennie R, Sand C, Porter S. The emergence of caspofungin resistance during treatment of recurrent Candida glabrata candidaemia. In: 16th ESCMID, April 1-4, 2006. Nice, France. 2006;Abstr. P1204.Google Scholar
  60. 60.
    Dodgson KJ, Dodgson AR, Pujol D, Messer SA, Soll DR. Pfaller MA. Caspofungin resistant C glabrata Clin Microbiol Infect. 2005;11:364.Google Scholar
  61. 61.
    Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS. Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint. Antimicrob Agents Chemother. 2009;53:3690–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Garcia-Effron G, Chua DJ, Tomada JR, et al. Novel FKS mutations associated with echinocandin resistance in Candida species. Antimicrob Agents Chemother. 2010;54:2225–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Sun HY, Singh N. Characterization of breakthrough invasive mycoses in echinocandin recipients: an evidence-based review. Int J Antimicrob Agents. 2010;35:211–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Katiyar S, Pfaller M, Edlind T. Candida albicans and Candida glabrata clinical isolates exhibiting reduced echinocandin susceptibility. Antimicrob Agents Chemother. 2006;50:2892–4.PubMedCrossRefGoogle Scholar
  65. 65.
    Thompson III GR, Wiederhold NP, Vallor AC, Villareal NC, Lewis Jr 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.PubMedCrossRefGoogle Scholar
  66. 66.
    Chandwani S, Wentworth C, Burke TA, Patterson TF. Utilization and dosage pattern of echinocandins for treatment of fungal infections in US hospital practice. Curr Med Res Opin. 2009;25:385–93.PubMedCrossRefGoogle Scholar
  67. 67.
    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.PubMedCrossRefGoogle Scholar
  68. 68.
    Vandeputte P, Pineau L, Larcher G, et al. Molecular mechanisms of resistance to 5-fluorocytosine in laboratory mutants of Candida glabrata. Mycopathologia. 2011;171:11–21.PubMedCrossRefGoogle Scholar
  69. 69.
    Kaur R, Domergue R, Zupancic ML, Cormack BP. A yeast by any other name: Candida glabrata and its interaction with the host. Curr Opin Microbiol. 2005;8:378–84.PubMedCrossRefGoogle Scholar
  70. 70.
    Pappas PG. Candidemia in the intensive care unit: miles to go before we sleep. Crit Care Med. 2011;39:884–5.PubMedCrossRefGoogle Scholar
  71. 71.
    Anderson JB. Evolution of antifungal-drug resistance: mechanisms and pathogen fitness. Nat Rev Microbiol. 2005;3:547–56.PubMedCrossRefGoogle Scholar
  72. 72.
    Andersson DI. The biological cost of mutational antibiotic resistance: any practical conclusions? Curr Opin Microbiol. 2006;9:461–5.PubMedCrossRefGoogle Scholar
  73. 73.
    Clancy CJ, Nguyen MH. At what cost echinocandin resistance? J Infect Dis. 2011;204:499–501.PubMedCrossRefGoogle Scholar
  74. 74.
    Arendrup MC, Perlin DS, Jensen RH, Howard SJ, Goodwin J, Hope W. Differential in vivo activity of anidulafungin, caspofungin and micafungin against C. glabrata with and without FKS resistance mutations. Antimicrob Agents Chemother. 2012;56:2435–42.Google Scholar
  75. 75.
    • Ben-Ami R, Garcia-Effron G, Lewis RE, et al. Fitness and Virulence Costs of Candida albicans FKS1 Hot Spot Mutations Associated With Echinocandin Resistance. J Infect Dis. 2011; 204:626-635. A novel and important use of an in vivo fly model to assess fitness and virulence costs of FKS mutations in C. albicans. Google Scholar
  76. 76.
    Zhao Y, Paak S, Delmas G, Gamarra MS, Perlin DS. Fitness costs of Candida glabrata FKS mutations associated with echinocandin resistance. In: 51st ICAAC, September 12-15, 2011. Chicago, IL, USA. 2011;Abstr. M-394.Google Scholar
  77. 77.
    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.PubMedCrossRefGoogle Scholar
  78. 78.
    • Ferrari S, Sanguinetti M, Torelli R, Posteraro B, Sanglard D. Contribution of CgPDR1-regulated genes in enhanced virulence of azole-resistant Candida glabrata. PLoS One. 2011; 6:e17589. An important illustration of the role of GOF mutations in virulence and azole resistance in C. glabrata. Google Scholar
  79. 79.
    Ferrari S, Sanguinetti M, De Bernardis F, et al. Loss of mitochondrial functions associated with azole resistance in Candida glabrata results in enhanced virulence in mice. Antimicrob Agents Chemother. 2011;55:1852–60.PubMedCrossRefGoogle Scholar
  80. 80.
    Edlind T, Shiffrin E, Vermitsky J, Katiyar S. Evidence for a hypervirulent, hypermutable Candida glabrata genotype. In: 51st ICAAC, September 12-15, 2011. Chicago, IL, USA. 2011;Abstr. M-295.Google Scholar
  81. 81.
    Sanglard D, Odds FC. Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences. Lancet Infect Dis. 2002;2:73–85.PubMedCrossRefGoogle Scholar
  82. 82.
    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
  83. 83.
    Berila N, Borecka S, Dzugasova V, Bojnansky J, Subik J. Mutations in the CgPDR1 and CgERG11 genes in azole-resistant Candida glabrata clinical isolates from Slovakia. Int J Antimicrob Agents. 2009;33:574–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Posteraro B, Sanguinetti M, Fiori B, et al. Caspofungin activity against clinical isolates of azole cross-resistant Candida glabrata overexpressing efflux pump genes. J Antimicrob Chemother. 2006;58:458–61.PubMedCrossRefGoogle Scholar
  85. 85.
    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.PubMedCrossRefGoogle Scholar
  86. 86.
    Kanafani ZA, Perfect JR. Antimicrobial resistance: resistance to antifungal agents: mechanisms and clinical impact. Clin Infect Dis. 2008;46:120–8.PubMedCrossRefGoogle Scholar
  87. 87.
    Peman J, Canton E, Espinel-Ingroff A. Antifungal drug resistance mechanisms. Expert Rev Anti Infect Ther. 2009;7:453–60.PubMedCrossRefGoogle Scholar
  88. 88.
    Ghannoum MA, Rice LB. Antifungal agents: Mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin Microbiol Rev. 1999;12:501–17.PubMedGoogle Scholar
  89. 89.
    Pfaller MA, Diekema DJ. Epidemiology of invasive candidiasis: A persistent public health problem. Clin Microbiol Rev. 2007;20:133–63.PubMedCrossRefGoogle Scholar
  90. 90.
    Pfaller MA, Messer SA, Bolmstrom A. Evaluation of Etest for determining in vitro susceptibility of yeast isolates to amphotericin B. Diagn Microbiol Infect Dis. 1998;32:223–7.PubMedCrossRefGoogle Scholar
  91. 91.
    Rex JH, Pfaller MA. Has antifungal susceptibility testing come of age? Clin Infect Dis. 2002;35:982–9.PubMedCrossRefGoogle Scholar
  92. 92.
    Sheehan DJ, Hitchcock CA, Sibley CM. Current and emerging azole antifungal agents. Clin Microbiol Rev. 1999;12:40–79.PubMedGoogle Scholar
  93. 93.
    Redding SW, Kirkpatrick WR, Saville S, et al. Multiple patterns of resistance to fluconazole in Candida glabrata isolates from a patient with oropharyngeal candidiasis receiving head and neck radiation. J Clin Microbiol. 2003;41:619–22.PubMedCrossRefGoogle Scholar
  94. 94.
    Niimi K, Maki K, Ikeda F, et al. Overexpression of Candida albicans CDR1, CDR2, or MDR1 does not produce significant changes in echinocandin susceptibility. Antimicrob Agents Chemother. 2006;50:1148–55.PubMedCrossRefGoogle Scholar
  95. 95.
    Vermes A, Guchelaar HJ, Dankert J. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother. 2000;46:171–9.PubMedCrossRefGoogle Scholar
  96. 96.
    Edlind TD, Katiyar SK. Mutational analysis of flucytosine resistance in Candida glabrata. Antimicrob Agents Chemother. 2010;54:4733–8.PubMedCrossRefGoogle Scholar
  97. 97.
    Cowen LE, Kohn LM, Anderson JB. Divergence in fitness and evolution of drug resistance in experimental populations of Candida albicans. J Bacteriol. 2001;183:2971–8.PubMedCrossRefGoogle Scholar
  98. 98.
    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.PubMedCrossRefGoogle Scholar
  99. 99.
    Cormack BP, Falkow S. Efficient homologous and illegitimate recombination in the opportunistic yeast pathogen Candida glabrata. Genetics. 1999;151:979–87.PubMedGoogle Scholar
  100. 100.
    Muller H, Thierry A, Coppée JY, et al. Genomic polymorphism in the population of Candida glabrata: gene copy-number variation and chromosomal translocations. Fungal Genet Biol. 2009;46:264–76.PubMedCrossRefGoogle Scholar
  101. 101.
    Poláková S, Blume C, Zárate JA, et al. Formation of new chromosomes as a virulence mechanism in yeast Candida glabrata. Proc Natl Acad Sci USA. 2009;106:2688–93.PubMedCrossRefGoogle Scholar
  102. 102.
    Shin JH, Chae MJ, Song JW, et al. Changes in karyotype and azole susceptibility of sequential bloodstream isolates from patients with Candida glabrata candidemia. J Clin Microbiol. 2007;45:2385–91.PubMedCrossRefGoogle Scholar
  103. 103.
    Selmecki A, Forche A, Berman J. Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science. 2006;313:367–70.PubMedCrossRefGoogle Scholar
  104. 104.
    Pfaller MA, Messer SA, Boyken L, Tendolkar S, Hollis RJ, Diekema DJ. Variation in susceptibility of bloodstream isolates of Candida glabrata to fluconazole according to patient age and geographic location. J Clin Microbiol. 2003;41:2176–9.PubMedCrossRefGoogle Scholar
  105. 105.
    Pfaller MA, Diekema DJ. Twelve years of fluconazole in clinical practice: global trends in species distribution and fluconazole susceptibility of bloodstream isolates of Candida. Clin Microbiol Infect. 2004;10 Suppl 1:11–23.PubMedCrossRefGoogle Scholar
  106. 106.
    Baddley JW, Smith AM, Moser SA, Pappas PG. Trends in frequency and susceptibilities of Candida glabrata bloodstream isolates at a university hospital. Diagn Microbiol Infect Dis. 2001;39:199–201.PubMedCrossRefGoogle Scholar
  107. 107.
    Diekema D, Arbefeville S, Boyken L, Kroeger J, Pfaller M. The changing epidemiology of healthcare-associated candidemia over three decades. Diagn Microbio Infect Dis. 2012;in press.Google Scholar
  108. 108.
    Malani A, Hmoud J, Chiu L, Carver PL, Bielaczyc A, Kauffman CA. Candida glabrata fungemia: Experience in a tertiary care center. Clin Infect Dis. 2005;41:975–81.PubMedCrossRefGoogle Scholar
  109. 109.
    • Sanglard D. Diagnosis of antifungal drug resistance mechanisms in fungal pathogens: Transcriptional gene regulation. Curr Fungal Infect Rep. 2011; 5:157-167. A very clear discussion of the role of transcriptional gene regulation in antifungal resistance.Google Scholar
  110. 110.
    Pfaller MA, Moet GJ, Messer SA, Jones RN, Castanheira M. Geographic variations in species distribution and echinocandin and azole antifungal resistance rates among Candida bloodstream infection isolates: report from the SENTRY Antimicrobial Surveillance Program (2008 to 2009). J Clin Microbiol. 2011;49:396–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Michael A. Pfaller
    • 1
    • 2
  • Mariana Castanheira
    • 1
  • Shawn R. Lockhart
    • 3
  • Ronald N. Jones
    • 1
  1. 1.JMI LaboratoriesNorth LibertyUSA
  2. 2.University of IowaIowa CityUSA
  3. 3.Mycotic Diseases BranchCenters for Disease Control and PreventionAtlantaUSA

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