Drugs

, Volume 73, Issue 6, pp 495–504

Cryptococcal Infections: Changing Epidemiology and Implications for Therapy

Current Opinion

Abstract

Although the incidence of HIV-associated cryptococcosis has decreased in developed countries since the introduction of antiretroviral therapy, this disease continues to cause significant morbidity and mortality in sub-Saharan Africa among patients with AIDS. Important strides have been made in an attempt to decrease the burden of disease, particularly the development of the lateral flow assay cryptococcal antigen (LFA CrAg) as a diagnostic tool in resource-limited settings, coupled with the introduction of pre-emptive treatment with fluconazole for HIV-positive patients at risk for cryptococcosis with a positive LFA CrAg. Among solid organ transplant recipients, recent prospective studies have identified cryptococcosis as the third most common invasive fungal infection, and progress is being made toward earlier diagnosis and more effective therapy. Finally, the Cryptococcus gattii outbreak in British Columbia, Canada and the US Pacific Northwest is providing important new insights into the emergence of this pathogen in geographic areas previously considered low risk for acquisition of infection. Understanding the similarities and differences among C. gattii and C. neoformans infections will provide critical insights into the behavior of these organisms in the human host. Both pathogens affect immunocompetent and immunosuppressed hosts, causing pulmonary, central nervous system and widely disseminated infections. Treatment recommendations in the future will necessarily take into account the site of infection, clinical severity of the infection, Cryptococcus species, host immune status and economic resources.

References

  1. 1.
    Baddley JW, Dismukes WE. Cryptococcosis. In: Kauffman CA, Pappas PG, Sobel JD, Dismukers WE, editors. Essentials of clinical mycology. 2nd ed. New York: Springer; 2011. p. 207–26.Google Scholar
  2. 2.
    Ikeda R, Shinoda T, Fukuzawa Y, et al. Antigenic characterization of Cryptococcus neoformans serotypes and its application to serotyping of clinical isolates. J Clin Microbiol. 1982;36:22–9.Google Scholar
  3. 3.
    Kwon-Chung KJ, Boekhout T, Fell JW, et al. Proposal to conserve the name Cryptococcus gattii against C. hondurianus and C. bacillisporus (Basidiomycota, Hymenomycetes, Trenomellomycetidae). Taxon. 2002;51:804–086.Google Scholar
  4. 4.
    Franzot SP, Salkin IF, Casadevall A. Cryptococcus neoformans var. Grubii: Separate varietal status for Cryptococcus neoformans serotype a isolates. J Clin Microbiol. 1999;37:838–40.PubMedGoogle Scholar
  5. 5.
    Sanfelice F. Contributo alle morfologia e biologia dei blastomiceti che si sviluppano nei succhi di alcuni frutti. Ann Isto Igiene R Univ Roma. 1894;4:463–95.Google Scholar
  6. 6.
    Dromer F, Mathoulin-Pelissier S, Fontanet A, Ronin O, Dupont B, Lortholary O, French Cryptococcosis Study G. Epidemiology of HIV-associated cryptococcosis in France (1985–2001): comparison of the pre and post-HAART eras. AIDS. 2004;18:555–62.PubMedCrossRefGoogle Scholar
  7. 7.
    Kaplan JE, Hanson D, Dworkin MS, Frederick T, Bertolli J, Lindegren ML, et al. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis. 2000;30(Suppl 1):S5–14.PubMedCrossRefGoogle Scholar
  8. 8.
    Mirza SA, Phelan M, Rimland D, Graviss E, Hamill R, Brandt ME, et al. The changing epidemiology of cryptococcosis: an update from population-based active surveillance in 2 large metropolitan areas, 1992–2000. Clin Infect Dis. 2003;36:789–94.PubMedCrossRefGoogle Scholar
  9. 9.
    van Elden LJ, Walenkamp AM, Lipovsky MM, Reiss P, Meis JF, de Marie S, et al. Declining number of patients with cryptococcosis in the Netherlands in the era of highly active antiretroviral therapy. AIDS. 2000;14:2787–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Park BJ, Wannemuehler KA, Marston BJ, et al. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS. 2009;23(4):525–30.PubMedCrossRefGoogle Scholar
  11. 11.
    Lawn SD, Harries AD, Anglaret X, et al. Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa. AIDS. 2008;22(15):1897–908.PubMedCrossRefGoogle Scholar
  12. 12.
    Mabey D, Peeling RW, Ustianowski A, Perkins MD. Diagnostics for the developing world. Nat Rev Microbiol. 2004;2:231–40.PubMedCrossRefGoogle Scholar
  13. 13.
    WHO. Mapping the landscape of diagnostics for sexually transmitted infections. Key findings and recommendations. UNICEF/UNDP/World Bank/WHO, 2004.Google Scholar
  14. 14.
    Lindsley MD, Mekha N, Baggett HC, et al. Evaluation of a newly developed lateral flow immunoassay for the diagnosis of cryptococcosis. Clin Infect Dis. 2011;53(4):321–5.PubMedCrossRefGoogle Scholar
  15. 15.
    Jarvis JN, Percival A, Bauman S, et al. Evaluation of a novel point-of-care cryptococcal antigen test on serum, plasma, and urine from patients with HIV-associated cryptococcal meningitis. Clin Infect Dis. 2011;53(10):1019–23.PubMedCrossRefGoogle Scholar
  16. 16.
    Binnicker MJ, Jespersen DJ, Bestrom JE, et al. Comparison of four assays for the detection of cryptococcal antigen. Clin Vaccine Immunol. 2012;19(12):1988–90.Google Scholar
  17. 17.
    Jarvis JN, Meintjes G, Wood R, et al. Testing but not treating: missed opportunities and lost lives in the South African antiretroviral therapy programme. AIDS. 2010;24(8):1233–5.PubMedCrossRefGoogle Scholar
  18. 18.
    Roy M, Chiller T. Preventing deaths from cryptococcal meningitis: from bench to bedside. Expert Rev Anti Infect Ther. 2011;9(9):715–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Micol R, Lortholary O, Sar B, et al. Prevalence, determinants of positivity, and clinical utility of cryptococcal antigenemia in Cambodian HIV-infected patients. J Acquir Immune Defi c Syndr. 2007;45:555–9.CrossRefGoogle Scholar
  20. 20.
    Jarvis JN, Lawn SD, Vogt M, Bangani N, Wood R, Harrison TS. Screening for cryptococcal antigenemia in patients accessing an antiretroviral treatment program in South Africa. Clin Infect Dis. 2009;48:856–62.PubMedCrossRefGoogle Scholar
  21. 21.
    Meya DB, Manabe YC, Castelnuovo B, et al. Cost-eff ectiveness of serum cryptococcal antigen screening to prevent deaths among HIV-infected persons with a CD4 + cell count < or = 100 cells/microL who start HIV therapy in resource-limited settings. Clin Infect Dis. 2010;51:448–55.PubMedCrossRefGoogle Scholar
  22. 22.
    Rajasingham R, Meya DB, Boulware DR. Integrating cryptococcal antigen screening and pre-emptive treatment into routine HIV care. J Acquir Immune Defic Syndr. 2012;59(5):e85–91.PubMedCrossRefGoogle Scholar
  23. 23.
    Jarvis JN, Lawn SD, Wood R, et al. Cryptococcal antigen screening for patients initiating antiretroviral therapy: time for action. Clin Infect Dis. 2010;51(12):1463–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Jarvis JN, Govender N, Chiller T, et al. Cryptococcal antigen screening and preemptive therapy in patients initiating antiretroviral therapy in resource-limited settings: a proposed algorithm for clinical implementation. J Int Assoc Physicians AIDS Care (Chic). 2012;11(6):374–9.Google Scholar
  25. 25.
    Rajasingham R, Boulware DR. Reconsidering cryptococcal antigen screening in the U.S. among persons with CD4 <100 cells/mcL. Clin Infect Dis. 2012;55(12):1742–4.Google Scholar
  26. 26.
    Chang LW, Phipps WT, Kennedy GE, Rutherford GW. Antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV. Cochrane Database Syst Rev. 2005;3:CD004773.Google Scholar
  27. 27.
    Parkes-Ratanshi R, Wakeham K, Levin J, et al. Primary prophylaxis of cryptococcal disease with fluconazole in HIV-positive Ugandan adults: a double-blind, randomised, placebo-controlled trial. Lancet Infect Dis. 2011;11(12):933–41.PubMedCrossRefGoogle Scholar
  28. 28.
    Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2010;50(3):291–322.PubMedCrossRefGoogle Scholar
  29. 29.
    World Health Organization (2011) Rapid advice: diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children. Geneva: World Health Organization. Available: http://whqlibdoc.who.int/publications/2011/9789241502979_eng.pdf. Accessed 2 Nov 2012.
  30. 30.
    van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med. 1997;337:15–21.PubMedCrossRefGoogle Scholar
  31. 31.
    Brouwer AE, Rajanuwong A, Chierakul W, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomized trial. Lancet. 2004;363:1764–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Bicanic T, Muzoora C, Brouwer AE, et al. Independent association between rate of clearance of infection and clinical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients. Clin Infect Dis. 2009;49:702–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Dromer F, Bernede-Bauduin C, Guillemot D, Lortholary O. Major role for amphotericin B-flucytosine combination in severe cryptococcosis. PLoS ONE. 2008;3:1–9.CrossRefGoogle Scholar
  34. 34.
    Day JN, Chau TTH, Dung NT, Mai PP, Phu NH, et al. (2011) Combination antifungal therapy for HIV associated cryptococcal meningitis [abstract]. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy, 17–20 September 2011; Chicago, IL, United States.Google Scholar
  35. 35.
    Pappas PG, Chetchotisakd P, Larsen RA, et al. A phase II randomized trial of amphotericin B alone or combined with fluconazole in the treatment of HIV-associated cryptococcal meningitis. Clin Infect Dis. 2009;48(12):1775–83.PubMedCrossRefGoogle Scholar
  36. 36.
    Loyse A, Wilson D, Meintjes G, et al. Comparison of the early fungicidal activity of high-dose fluconazole, voriconazole, and flucytosine as second-line drugs given in combination with amphotericin B for the treatment of HIV-associated cryptococcal meningitis. Clin Infect Dis. 2012;54(1):121–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Shoham S, Cover C, Donegan N, et al. Cryptococcus neoformans meningitis at 2 hospitals in Washington, D.C.: adherence of health care providers to published practice guidelines for the management of cryptococcal disease. Clin Infect Dis. 2005;40:477–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Pappas PG. Managing cryptococcal meningitis is about handling the pressure. Clin Infect Dis. 2005;40:480–2.PubMedCrossRefGoogle Scholar
  39. 39.
    Pappas PG, Bustamante B, Ticona E, et al. Recombinant interferon- gamma 1b as adjunctive therapy for AIDS-related acute cryptococcal meningitis. J Infect Dis. 2004;189(12):2185–91.PubMedCrossRefGoogle Scholar
  40. 40.
    Jarvis JN, Meintjes G, Rebe K, et al. Adjunctive interferon-γ immunotherapy for the treatment of HIV-associated cryptococcal meningitis: a randomized controlled trial. AIDS. 2012;26(9):1105–13.PubMedCrossRefGoogle Scholar
  41. 41.
    Muzoora CK, Kabanda T, Ortu G, et al. Short course amphotericin B with high dose fluconazole for HIV-associated cryptococcal meningitis. J Infect. 2012;64(1):76–81.PubMedCrossRefGoogle Scholar
  42. 42.
    Nussbaum JC, Jackson A, Namarika D, et al. Combination flucytosine and high-dose fluconazole compared with fluconazole monotherapy for the treatment of cryptococcal meningitis: a randomized trial in Malawi. Clin Infect Dis. 2010;50(3):338–44.PubMedCrossRefGoogle Scholar
  43. 43.
    Rajasingham R, Rolfes MA, Birkenkamp KE, Meya DB, Boulware DR. Cryptococcal meningitis treatment strategies in resource-limited settings: a cost-effectiveness analysis. PLoS Med. 2012;9(9):e1001316. doi:10.1371/journal.pmed.1001316.PubMedCrossRefGoogle Scholar
  44. 44.
    Zolopa AR, Andersen J, Komarow L, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS ONE. 2009;4:1–10.CrossRefGoogle Scholar
  45. 45.
    Makadzange AT, Ndhlovu CE, Takarinda K, et al. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. Clin Infect Dis. 2010;50(11):1532–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Bisson GP, Molefi M, Bellamy S, et al. Early versus delayed antiretroviral therapy and cerebrospinal fluid fungal clearance in adults with HIV and cryptococcal meningitis. Clin Infect Dis. 2013;56(8):1165–73.Google Scholar
  47. 47.
    Organ Procurement and Transplantation Network and Scientific Registry of Transplant Recipients 2010 data report. Am J Transplant. 2012;12 (Suppl 1):1–156.Google Scholar
  48. 48.
    Singh N, Husain S, De Vera M, et al. Cryptococcus neoformans infection in patients with cirrhosis. Including liver transplant candidates. Medicine (Baltimore). 2004;83(3):188–92.CrossRefGoogle Scholar
  49. 49.
    Sifri CD, Sun HY, Cacciarelli TV, et al. Pretransplant cryptococcosis and outcome after liver transplantation. Liver Transpl. 2010;16(4):499–502.PubMedGoogle Scholar
  50. 50.
    Singh N, How I. Treat cryptococcosis in organ transplant recipients. Transplantation. 2012;93(1):17–21.PubMedCrossRefGoogle Scholar
  51. 51.
    Grossi PA, Fishman JA, AST Infectious Disease Community of Practice. Donor-derived infections in solid organ transplant recipients. Am J Transplant. 2009;9(Suppl 4):S19–26.PubMedCrossRefGoogle Scholar
  52. 52.
    Grossi PA, Costa AN, Fehily D, et al. Infections and organ transplantation: new challenges for prevention and treatment—a colloquium. Transplantation. 2012;93(5 Suppl):S4–39.PubMedCrossRefGoogle Scholar
  53. 53.
    Fishman JA, Greenwald MA, Grossi PA. Transmission of infection with human allografts: essential considerations in donor screening. Clin Infect Dis. 2012;55(5):720–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Sun HY, Alexander BD, Lortholary O, et al. Unrecognized pretransplant and donor-derived cryptococcal disease in organ transplant recipients. Clin Infect Dis. 2010;51(9):1062–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Baddley JW, Schain DC, Gupte AA, et al. Transmission of Cryptococcus neoformans by organ transplantation. Clin Infect Dis. 2011;52(4):e94–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Pappas PG, Alexander BD, Andes DR, et al. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis. 2010;50(8):1101–11.PubMedCrossRefGoogle Scholar
  57. 57.
    Singh N, Forrest G. AST Infectious Diseases Community of Practice. Cryptococcosis in solid organ transplant recipients. Am J Transplant. 2009;9(Suppl 4):S192–8.PubMedCrossRefGoogle Scholar
  58. 58.
    Singh N, Lortholary O, Alexander BD, et al. Antifungal management practices and evolution of infection in organ transplant recipients with Cryptococcus neoformans infection. Transplantation. 2005;80(8):1033–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Pappas PG, Perfect JR, Cloud GA, et al. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin Infect Dis. 2001;33(5):690–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Kiertiburanakul S, Wirojtananugoon S, Pracharktam R, et al. Cryptococcosis in human immunodeficiency virus-negative patients. Int J Infect Dis. 2006;10(1):72–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Jongwutiwes U, Sungkanuparph S, Kiertiburanakul S. Comparison of clinical features and survival between cryptococcosis in human immunodeficiency virus (HIV)-positive and HIV-negative patients. Jpn J Infect Dis. 2008;61(2):111–5.PubMedGoogle Scholar
  62. 62.
    Yuchong C, Fubin C, Jianghan C, et al. Cryptococcosis in China (1985–2010): review of cases from Chinese database. Mycopathologia. 2012;173(5–6):329–35.PubMedCrossRefGoogle Scholar
  63. 63.
    Ecevit IZ, Clancy CJ, Schmalfuss IM, et al. The poor prognosis of central nervous system cryptococcosis among nonimmunosuppressed patients: a call for better disease recognition and evaluation of adjuncts to antifungal therapy. 2006;42:1443–7.Google Scholar
  64. 64.
    Wu SX, Guo NR, Li XF, et al. Human pathogenic fungi in China—emerging trends from ongoing national survey for 1986, 1996, and 2006. Mycopathologia. 2011;171(6):387–93.PubMedCrossRefGoogle Scholar
  65. 65.
    Brizendine KD, Baddley JW, Pappas PG. Pulmonary cryptococcosis. Semin Respir Crit Care Med. 2011;32(6):727–34.PubMedCrossRefGoogle Scholar
  66. 66.
    Shaunak S, Schell WA, Perfect JR. Cryptococcal meningitis with normal cerebrospinal fluid. J Infect Dis. 1989;160(5):912.PubMedCrossRefGoogle Scholar
  67. 67.
    Kwon-Chung KJ, Varma A. Do major species concepts support one, two or more species within Cryptococcus neoformans? FEMS Yeast Res. 2006;6(4):574–87.PubMedCrossRefGoogle Scholar
  68. 68.
    Sorrell TC, Chen SC, Ruma P, et al. Concordance of clinical and environmental isolates of Cryptococcus neoformans var. gattii by random amplification of polymorphic DNA analysis and PCR fingerprinting. J Clin Microbiol. 1996;34:1253–60.PubMedGoogle Scholar
  69. 69.
    Byrnes EJ 3rd, Bildfell RJ, Frank SA, et al. Molecular evidence that the range of the Vancouver Island outbreak of Cryptococcus gattii infection has expanded into the Pacific Northwest in the United States. J Infect Dis. 2009;199(7):1081–6.PubMedCrossRefGoogle Scholar
  70. 70.
    Kwon-Chung KJ, Polacheck I, Bennett JE. Improvedm ediumf or separation of Cryptococcus neoformans var. neoformans (serotypes A and D) and Cryptococcus neoformans var. gattii (serotypes B and C). J Clin Microbiol. 1982;15:535–7.PubMedGoogle Scholar
  71. 71.
    Kwon-Chung KJ, Bennett JE. High prevalence of Cryptococcus neoformans var. gattii in tropical and subtropical regions. Zentralbl. Bakteriol. Mikrobiol Hyg A. 1984;257:213–8.PubMedGoogle Scholar
  72. 72.
    Kwon-Chung KJ, Bennett JE. Epidemiologic differences between the two varieties of Cryptococcus neoformans. Am J Epidemiol. 1984;120(1):123–30.PubMedGoogle Scholar
  73. 73.
    Stephen C, Lester S, Black W, et al. Multispecies outbreak of cryptococcosis on southern Vancouver Island, British Columbia. Can Vet J. 2002;43(10):792–4.PubMedGoogle Scholar
  74. 74.
    Galanis E, MacDougall L. Epidemiology of Cryptococcus gattii, British Columbia, Canada, 1999–2007. Emerg Infect Dis. 2010;16:251–7.PubMedCrossRefGoogle Scholar
  75. 75.
    MacDougall L, Kidd SE, Galanis E, et al. Spread of Cryptococcus gattii in British Columbia, Canada, and detection in the Pacific Northwest, USA. Emerg Infect Dis. 2007;13:42–50.PubMedCrossRefGoogle Scholar
  76. 76.
    Centers for Disease Control and Prevention (CDC). Emergence of Cryptococcus gattii—Pacific Northwest, 2004–2010. MMWR Morb Mortal Wkly Rep. 2010;59:865–8.Google Scholar
  77. 77.
    Harris JR, Lockhart SR, Debess E, et al. Cryptococcus gattii in the United States: clinical aspects of infection with an emerging pathogen. Clin Infect Dis. 2011;53(12):1188–95.PubMedCrossRefGoogle Scholar
  78. 78.
    Chen S, Sorrell T, Nimmo G, Speed B, Currie B, Ellis D, Marriott D, Pfeiffer T, Parr D, Byth K. Epidemiology and host- and variety-dependent characteristics of infection due to Cryptococcus neoformans in Australia and New Zealand. Australasian Cryptococcal Study Group. Clin Infect Dis. 2000;31:499–508.PubMedCrossRefGoogle Scholar
  79. 79.
    Mitchell DH, Sorrell TC, Allworth AM, Heath CH, McGregor AR, Papanaoum K, Richards MJ, Gottlieb T. Cryptococcal disease of the CNS in immunocompetent hosts: influence of cryptococcal variety on clinical manifestations and outcome. Clin Infect Dis. 1995;20:611–6.PubMedCrossRefGoogle Scholar
  80. 80.
    Speed B, Dunt D. Clinical and host differences between infections with the two varieties of Cryptococcus neoformans. Clin Infect Dis. 1995;21:28–34.PubMedCrossRefGoogle Scholar
  81. 81.
    MacDougall L, Fyfe M, Romney M, Starr M, Galanis E. Risk factors for Cryptococcus gattii infection, British Columbia, Canada. Emerg Infect Dis. 2011;17:193–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Marr KA. Cryptococcus gattii: the tip of the iceberg. Clin Infect Dis. 2011;53(12):1196–8.PubMedCrossRefGoogle Scholar
  83. 83.
    Harris JR, Lockhart SR, Chiller T. Letter re: Marr editorial. Clin Infect Dis. 2012;54(7):1038–9.PubMedCrossRefGoogle Scholar
  84. 84.
    Thompson GR 3rd, Wiederhold NP, Fothergill AW, et al. Antifungal susceptibilities among different serotypes of Cryptococcus gattii and Cryptococcus neoformans. Antimicrob Agents Chemother. 2009;53(1):309–11.PubMedCrossRefGoogle Scholar
  85. 85.
    Iqbal N, DeBess EE, Wohrle R, et al. Correlation of genotype and in vitro susceptibilities of Cryptococcus gattii strains from the Pacific Northwest of the United States. J Clin Microbiol. 2010;48(2):539–44.PubMedCrossRefGoogle Scholar
  86. 86.
    Hagen F, Illnait-Zaragozi MT, Bartlett KH, et al. In vitro antifungal susceptibilities and amplified fragment length polymorphism genotyping of a worldwide collection of 350 clinical, veterinary, and environmental Cryptococcus gattii isolates. Antimicrob Agents Chemother. 2010;54(12):5139–45.PubMedCrossRefGoogle Scholar
  87. 87.
    Chong HS, Dagg R, Malik R, et al. In vitro susceptibility of the yeast pathogen cryptococcus to fluconazole and other azoles varies with molecular genotype. J Clin Microbiol. 2010;48(11):4115–20.PubMedCrossRefGoogle Scholar
  88. 88.
    Espinel-Ingroff A, Chowdhary A, Cuenca-Estrella M, et al. Cryptococcus neoformansCryptococcus gattii species complex: an international study of wild-type susceptibility endpoint distributions and epidemiological cutoff values for amphotericin B and flucytosine. Antimicrob Agents Chemother. 2012;56(6):3107–13.PubMedCrossRefGoogle Scholar
  89. 89.
    Trilles L, Meyer W, Wanke B, et al. Correlation of antifungal susceptibility and molecular type within the Cryptococcus neoformans/C. gattii species complex. Med Mycol. 2012;50(3):328–32.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Division of Infectious Diseases, Department of MedicineUniversity of Alabama at BirminghamBirminghamUSA

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