1887

Chapter 12 : Fungal Biofilms: Agents of Disease and Drug Resistance

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $15.00

Preview this chapter:
Zoom in
Zoomout

Fungal Biofilms: Agents of Disease and Drug Resistance, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555815776/9781555813680_Chap12-1.gif /docserver/preview/fulltext/10.1128/9781555815776/9781555813680_Chap12-2.gif

Abstract:

Bacterial biofilms and their role in disease have been investigated in detail over 15 to 20 years, but research on fungal biofilms has traditionally lagged. Although other fungal species have been associated with biofilm formation, this chapter concentrates on since it is the fungal system that has received the most attention to date regarding its biofilm-forming ability. Different mechanisms may be responsible for the intrinsic resistance of biofilms to antimicrobials. These include (i) effects of the biofilm matrix on penetration of drugs; (ii) decreased growth rate and nutrient limitation; (iii) expression of resistance genes, particularly those encoding efflux pumps; and (iv) presence of “persister” cells. Several studies have examined the effects of growth rate and nutrient limitation in relation to drug resistance in . In addition, an intriguing observation is that anaerobic growth leads to high levels of antifungal drug resistance in ; this could contribute to the intrinsic resistance in cells within the biofilms, where oxygen limitation may occur. Importantly, multiple antifungal agents can be substrates for some of these transporters, and thus their overexpression leads to cross-resistance among different drugs. The biofilm mode of growth results in antifungal drug resistance and protection from host defenses, which carry important clinical repercussions. In addition, it is likely that biofilm infections involve bacteria and various species in a polymicrobial consortium. In these complex communities, cell-cell communication, across both kingdom and species, may modulate gene expression, including drug resistance mechanism.

Citation: Ramage G, Ghannoum M, LÓpez-Ribot J. 2006. Fungal Biofilms: Agents of Disease and Drug Resistance, p 177-185. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch12
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Image of Figure 1.
Figure 1.

Diagram depicting the stages of biofilm formation. (A) Initial attachment of yeast cells. (B) Formation of a basal monolayer of yeast cells. (C) Proliferation of micro-colonies and filamentation. (D) Further filamentation during maturation and encasement within exopolymeric material (note that synthesis of EPS starts early during biofilm formation [not depicted]).

Citation: Ramage G, Ghannoum M, LÓpez-Ribot J. 2006. Fungal Biofilms: Agents of Disease and Drug Resistance, p 177-185. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2.
Figure 2.

SEM image of a mature (48-h) biofilm. Biofilms are composed of yeast cells, pseudohyphae, and hyphae. Also visible are the remains of the exopolymeric matrix after dehydration due to SEM procedures. Bar, 10 μm.

Citation: Ramage G, Ghannoum M, LÓpez-Ribot J. 2006. Fungal Biofilms: Agents of Disease and Drug Resistance, p 177-185. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555815776.ch12
1. Adam, B.,, G. S. Baillie, and, L. J. Douglas. 2002. Mixed species biofilms of Candida albicans and Staphylococcus epidermidis. J. Med. Microbiol. 51:344349.
2. Alem, M. A., and, L. J. Douglas. 2004. Effects of aspirin and other nonsteroidal anti-inflammatory drugs on biofilms and planktonic cells of Candida albicans. Antimicrob. Agents Chemother. 48:4147.
3. Al-Fattani, M. A., and, L. J. Douglas. 2004. Penetration of Candida biofilms by antifungal agents. Antimicrob. Agents Chemother. 48:32913297.
4. Andes, D.,, J. Nett,, P. Oschel,, R. Albrecht,, K. Marchillo, and, A. Pitula. 2004. Development and characterization of an in vivo central venous catheter Candida albicans biofilm model. Infect. Immun. 72:60236031.
5. Bachmann, S. P.,, G. Ramage,, K. VandeWalle,, T. F. Patterson,, B. L. Wickes, and, J. L. Lopez-Ribot. 2003. Antifungal combinations against Candida albicans biofilms in vitro. Antimicrob. Agents Chemother. 47:36573659.
6. Bachmann, S. P.,, K. VandeWalle,, G. Ramage,, T. F. Patterson,, B. L. Wickes,, J. R. Graybill, and, J. L. Lopez-Ribot. 2002. In vitro activity of caspofungin against Candida albicans biofilms. Antimicrob. Agents Chemother. 46:35913596.
7. Baillie, G. S., and, L. J. Douglas. 1999. Candida biofilms and their susceptibility to antifungal agents. Methods Enzymol. 310:644656.
8. Baillie, G. S., and, L. J. Douglas. 1998. Effect of growth rate on resistance of Candida albicans biofilms to antifungal agents. Antimicrob. Agents Chemother. 42:19001905.
9. Baillie, G. S., and, L. J. Douglas. 1998. Iron-limited biofilms of Candida albicans and their susceptibility to amphotericin B. Antimicrob. Agents Chemother. 42:21462149.
10. Baillie, G. S., and, L. J. Douglas. 2000. Matrix polymers of Candida biofilms and their possible role in biofilm resistance to antifungal agents. J. Antimicrob. Chemother. 46:397403.
11. Baillie, G. S., and, L. J. Douglas. 1999. Role of dimorphism in the development of Candida albicans biofilms. J. Med. Microbiol. 48:671679.
12. Balzi, E., and, A. Goffeau. 1995. Yeast multidrug resistance: the PDR network. J. Bioenerg. Biomembr. 27:7176.
13. Beck-Sague, C., and, W. R. Jarvis. 1993. Secular trends in the epidemiology of nosocomial fungal infections in the United States, 1980–1990. National Nosocomial Infections Surveillance System. J. Infect. Dis. 167:12471251.
14. Brown, A. J., and, N. A. Gow. 1999. Regulatory networks controlling Candida albicans morphogenesis. Trends Microbiol. 7:333338.
15. Brown, A., J. P. 2002. Morphogenetic signaling pathways in Candida albicans, p. 95–106. In R. A. Calderone (ed.), Candida and Candidiasis. ASM Press, Washington, D.C.
16. Chaffin, W. L.,, J. L. Lopez-Ribot,, M. Casanova,, D. Gozalbo, and, J. P. Martinez. 1998. Cell wall and secreted proteins of Candida albicans: identification, function, and expression. Microbiol. Mol. Biol. Rev. 62:130180.
17. Chandra, J.,, D. M. Kuhn,, P. K. Mukherjee,, L. L. Hoyer,, T. McCormick, and, M. A. Ghannoum. 2001. Biofilm formation by the fungal pathogen Candida albicans: development, architecture, and drug resistance. J. Bacteriol. 183:53855394.
18. Chandra, J.,, P. K. Mukherjee,, S. D. Leidich,, F. F. Faddoul,, L. L. Hoyer,, L. J. Douglas, and, M. A. Ghannoum. 2001. Antifungal resistance of candidal biofilms formed on denture acrylic in vitro. J. Dent. Res. 80:903908.
19. Chen, H.,, M. Fujita,, Q. Feng,, J. Clardy, and, G. R. Fink. 2004. Tyrosol is a quorum-sensing molecule in Candida albicans. Proc. Natl. Acad. Sci. USA 101:50485052.
20. Costerton, J. W.,, K. J. Cheng,, G. G. Geesey,, T. I. Ladd,, J. C. Nickel,, M. Dasgupta, and, T. J. Marrie. 1987. Bacterial biofilms in nature and disease. Annu. Rev. Microbiol. 41:435464.
21. Costerton, J. W.,, Z. Lewandowski,, D. E. Caldwell,, D. R. Korber, and, H. M. Lappin-Scott. 1995. Microbial biofilms. Annu. Rev. Microbiol. 49:711745.
22. Costerton, J. W.,, P. S. Stewart, and, E. P. Greenberg. 1999. Bacterial biofilms: a common cause of persistent infections. Science 284:13181322.
23. Cremer, J.,, V. Vatou, and, I. Braveny. 1999. 2,4-(hydroxyphenyl)-ethanol, an antioxidative agent produced by Candida spp., impairs neutrophilic yeast killing in vitro. FEMS Microbiol. Lett. 170:319325.
24. Cristobal, R.,, C. E. Edmiston,, Jr., C., L. Runge-Samuelson,, H. A. Owen,, J. B. Firszt, and, P. A. Wackym. 2004. Fungal biofilm formation on cochlear implant hardware after antibiotic-induced fungal overgrowth within the middle ear. Pediatr. Infect. Dis. J. 23:774778.
25. Crump, J. A., and, P. J. Collignon. 2000. Intravascular catheter-associated infections. Eur. J. Clin. Microbiol. Infect. Dis. 19:18.
26. Del Sorbo, G., H. Schoonbeek, and, M. A. De Waard. 2000. Fungal transporters involved in efflux of natural toxic compounds and fungicides. Fungal Genet. Biol. 30:115.
27. Donlan, R. M. 2001. Biofilm formation: a clinically relevant microbiological process. Clin. Infect. Dis. 33:13871392.
28. Donlan, R. M. 2001. Biofilms and device-associated infections. Emerg. Infect. Dis. 7:277281.
29. Donlan, R. M. 2002. Biofilms: microbial life on surfaces. Emerg. Infect. Dis. 8:881890.
30. Douglas, L. J. 2003. Candida biofilms and their role in infection. Trends Microbiol. 11:3036.
31. Douglas, L. J. 2002. Medical importance of biofilms in Candida infections. Rev. Iberoam. Micol. 19:139143.
32. Dumitru, R.,, J. M. Hornby, and, K. W. Nickerson. 2004. Defined anaerobic growth medium for studying Candida albicans basic biology and resistance to eight antifungal drugs. Antimicrob. Agents Chemother. 48:23502354.
33. Dunne, W., M., Jr. 2002. Bacterial adhesion: seen any good biofilms lately? Clin. Microbiol. Rev. 15:155166.
34. Evans, D. J.,, M. R. Brown,, D. G. Allison, and, P. Gilbert. 1990. Susceptibility of bacterial biofilms to tobramycin: role of specific growth rate and phase in the division cycle. J. Antimicrob. Chemother. 25:585591.
35. Francois, P.,, P. Vaudaux, and, P. D. Lew. 1998. Role of plasma and extracellular matrix proteins in the physio-pathology of foreign body infections. Ann. Vasc. Surg. 12:3440.
36. Garcia-Sanchez, S.,, S. Aubert,, I. Iraqui,, G. Janbon,, J. M. Ghigo, and, C. d’Enfert. 2004. Candida albicans biofilms: a developmental state associated with specific and stable gene expression patterns. Eukaryot. Cell 3:536545.
37. Ghannoum, M. A. 1997. Susceptibility testing of fungi and correlation with clinical outcome. J. Chemother. 9(Suppl. 1):1924.
38. Ghannoum, M. A.,, J. H. Rex, and, J. N. Galgiani. 1996. Susceptibility testing of fungi: current status of correlation of in vitro data with clinical outcome. J. Clin. Microbiol. 34:489495.
39. Ghannoum, M. A., and, L. B. Rice. 1999. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin. Microbiol. Rev. 12:501517.
40. Gilbert, P.,, J. Das, and, I. Foley. 1997. Biofilm susceptibility to antimicrobials. Adv. Dent. Res. 11:160167.
41. Gow, N. A.,, A. J. Brown, and, F. C. Odds. 2002. Fungal morphogenesis and host invasion. Curr. Opin. Microbiol. 5:366371.
42. Green, C. B.,, G. Cheng,, J. Chandra,, P. Mukherjee,, M. A. Ghannoum, and, L. L. Hoyer. 2004. RT-PCR detection of Candida albicans ALS gene expression in the reconstituted human epithelium (RHE) model of oral candidiasis and in model biofilms. Microbiology 150:267275.
43. Gristina, A. G. 1987. Biomaterial-centered infection: microbial adhesion versus tissue integration. Science 237:15881595.
44. Gristina, A. G.,, Y. Shibata,, G. Giridhar,, A. Kreger, and, Q. N. Myrvik. 1994. The glycocalyx, biofilm, microbes, and resistant infection. Semin. Arthroplasty 5:160170.
45. Groll, A. H., and, T. J. Walsh. 2002. Antifungal chemotherapy: advances and perspectives. Swiss Med. Wkly. 132:303311.
46. Hall-Stoodley, L.,, J. W. Costerton, and, P. Stoodley. 2004. Bacterial biofilms: from the natural environment to infectious diseases. Nat. Rev. Microbiol. 2:95108.
47. Hawser, S. P.,, G. S. Baillie, and, L. J. Douglas. 1998. Production of extracellular matrix by Candida albicans biofilms. J. Med. Microbiol. 47:253256.
48. Hawser, S. P., and, L. J. Douglas. 1994. Biofilm formation by Candida species on the surface of catheter materials in vitro. Infect. Immun. 62:915921.
49. Higgins, C. F. 1992. ABC transporters: from microorganisms to man. Annu. Rev. Cell Biol. 8:67113.
50. Hogan, D. A., and, R. Kolter. 2002. Pseudomonas-Candida interactions: an ecological role for virulence factors. Science 296:22292232.
51. Hogan, D. A.,, A. Vik, and, R. Kolter. 2004. A Pseudomonas aeruginosa quorum-sensing molecule influences Candida albicans morphology. Mol. Microbiol. 54:12121223.
52. Holmes, A. R.,, R. D. Cannon, and, H. F. Jenkinson. 1995. Interactions of Candida albicans with bacteria and salivary molecules in oral biofilms. J. Ind. Microbiol. 15:208213.
53. Hornby, J. M.,, E. C. Jensen,, A. D. Lisec,, J. J. Tasto,, B. Jahnke,, R. Shoemaker,, P. Dussault, and, K. W. Nickerson. 2001. Quorum sensing in the dimorphic fungusCandida albicans is mediated by farnesol. Appl. Environ. Microbiol. 67:29822992.
54. Hoyle, B. D.,, J. Jass, and, J. W. Costerton. 1990. The biofilm glycocalyx as a resistance factor. J. Antimicrob. Chemother. 26:15.
55. Jabra-Rizk, M. A.,, W. A. Falkler, and, T. F. Meiller. 2004. Fungal biofilms and drug resistance. Emerg. Infect. Dis. 10:1419.
56. Kelly, M. T.,, D. M. MacCallum,, S. D. Clancy,, F. C. Odds,, A. J. Brown, and, G. Butler. 2004. The Candida albicans CaACE2 gene affects morphogenesis, adherence and virulence. Mol. Microbiol. 53:969983.
57. Khardori, N., and, M. Yassien. 1995. Biofilms in device-related infections. J. Ind. Microbiol. 15:141147.
58. Kjelleberg, S.,, S. Molin,, M. B. Miller, and, B. L. Bassler. 2002. Is there a role for quorum sensing signals in bacterial biofilms? Quorum sensing in bacteria. Curr. Opin. Microbiol. 5:254258.
59. Kohler, J. R., and, G. R. Fink. 1996. Candida albicans strains heterozygous and homozygous for mutations in mitogen-activated protein kinase signaling components have defects in hyphal development. Proc. Natl. Acad. Sci. USA 93:1322313228.
60. Kojic, E. M., and, R. O. Darouiche. 2004. Candida infections of medical devices. Clin. Microbiol. Rev. 17:255267.
61. Krueger, K. E.,, A. K. Ghosh,, B. P. Krom, and, R. L. Cihlar. 2004. Deletion of the NOT4 gene impairs hyphal development and pathogenicity in Candida albicans. Microbiology 150:229240.
62. Kruppa, M.,, B. P. Krom,, N. Chauhan,, A. V. Bambach,, R. L. Cihlar, and, R. A. Calderone. 2004. The two-component signal transduction protein Chk1p regulates quorum sensing in Candida albicans. Eukaryot. Cell 3:10621065.
63. Kuhn, D. M.,, J. Chandra,, P. K. Mukherjee, and, M. A. Ghannoum. 2002. Comparison of biofilms formed by Candida albicans and Candida parapsilosis on bioprosthetic surfaces. Infect. Immun. 70:878888.
64. Kuhn, D. M.,, T. George,, J. Chandra,, P. K. Mukherjee, and, M. A. Ghannoum. 2002. Antifungal susceptibility of Candida biofilms: unique efficacy of amphotericin B lipid formulations and echinocandins. Antimicrob. Agents Chemother. 46:17731780.
65. Kumamoto, C. A. 2002. Candida biofilms. Curr. Opin. Microbiol. 5:608611.
66. Lewis, K. 2001. Riddle of biofilm resistance. Antimicrob. Agents Chemother. 45:9991007.
67. Lewis, R. E.,, D. P. Kontoyiannis,, R. O. Darouiche,, I. I. Raad, and, R. A. Prince. 2002. Antifungal activity of amphotericin B, fluconazole, and voriconazole in an in vitro model of Candida catheter-related bloodstream infection. Antimicrob. Agents Chemother. 46:34993505.
68. Lewis, R. E.,, H. J. Lo,, I. I. Raad, and, D. P. Kontoyiannis. 2002. Lack of catheter infection by the efg1/efg1 cph1/cph1 double-null mutant, a Candida albicans strain that is defective in filamentous growth. Antimicrob. Agents Chemother. 46:11531155.
69. Li, F., and, S. P. Palecek. 2003. EAP1, a Candida albicans gene involved in binding human epithelial cells. Eukaryot. Cell 2:12661273.
70. Li, X.,, Z. Yan, and, J. Xu. 2003. Quantitative variation of biofilms among strains in natural populations of Candida albicans. Microbiology 149:353362.
71. Marger, M. D., and, M. H. Saier, Jr. 1993. A major super-family of transmembrane facilitators that catalyse uni-port, symport and antiport. Trends Biochem. Sci. 18:1320.
72. Mateus, C.,, S. A. Crow, Jr., and, D. G. Ahearn. 2004. Adherence of Candida albicans to silicone induces immediate enhanced tolerance to fluconazole. Antimicrob. Agents Chemother. 48:33583366.
73. Miller, M. B., and, B. L. Bassler. 2001. Quorum sensing in bacteria. Annu. Rev. Microbiol. 55:165199.
74. Millsap, K. W.,, R. Bos,, H. C. van der Mei, and, H. J. Busscher. 2001. Adhesive interactions between voice prosthetic yeast and bacteria on silicone rubber in the absence and presence of saliva. Antonie Leeuwenhoek 79:337343.
75. Mukherjee, P. K.,, J. Chandra,, D. M. Kuhn, and, M. A. Ghannoum. 2003. Mechanism of fluconazole resistance in Candida albicans biofilms: phase-specific role of efflux pumps and membrane sterols. Infect. Immun. 71:43334340.
76. O’Toole, G.,, H. B. Kaplan, and, R. Kolter. 2000. Biofilm formation as microbial development. Annu. Rev. Microbiol. 54:4979.
77. Raad, I.,, I. Chatzinikolaou,, G. Chaiban,, H. Hanna,, R. Hachem,, T. Dvorak,, G. Cook, and, W. Costerton. 2003. In vitro and ex vivo activities of minocycline and EDTA against microorganisms embedded in biofilm on catheter surfaces. Antimicrob. Agents Chemother. 47:35803585.
78. Ramage, G.,, S. Bachmann,, T. F. Patterson,, B. L. Wickes, and, J. L. Lopez-Ribot. 2002. Investigation of multidrug efflux pumps in relation to fluconazole resistance in Candida albicans biofilms. J. Antimicrob. Chemother. 49:973980.
79. Ramage, G.,, S. P. Saville,, B. L. Wickes, and, J. L. Lopez-Ribot. 2002. Inhibition of Candida albicans biofilm formation by farnesol, a quorum-sensing molecule. Appl. Environ. Microbiol. 68:54595463.
80. Ramage, G.,, K. Tomsett,, B. L. Wickes,, J. L. Lopez-Ribot, and, S. W. Redding. 2004. Denture stomatitis: a role for Candida biofilms. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 98:5359.
81. Ramage, G.,, K. Vande Walle,, B. L. Wickes, and, J. L. Lopez-Ribot. 2001. Biofilm formation by Candida dubliniensis. J. Clin. Microbiol. 39:32343240.
82. Ramage, G.,, K. Vande Walle,, B. L. Wickes, and, J. L. Lopez-Ribot. 2001. Standardized method for in vitro antifungal susceptibility testing of Candida albicans biofilms. Antimicrob. Agents Chemother. 45:24752479.
83. Ramage, G.,, K. VandeWalle,, S. P. Bachmann,, B. L. Wickes, and, J. L. Lopez-Ribot. 2002. In vitro pharmaco-dynamic properties of three antifungal agents against preformed Candida albicans biofilms determined by time-kill studies. Antimicrob. Agents Chemother. 46:36343636.
84. Ramage, G.,, K. VandeWalle,, J. L. Lopez-Ribot, and, B. L. Wickes. 2002. The filamentation pathway controlled by the Efg1 regulator protein is required for normal biofilm formation and development in Candida albicans. FEMS Microbiol. Lett. 214:95100.
85. Ramage, G.,, K. VandeWalle,, B. L. Wickes, and, J. L. Lopez-Ribot. 2001. Characteristics of biofilm formation by Candida albicans. Rev. Iberoam. Micol. 18:163170.
86. Ramage, G.,, B. L. Wickes, and, J. L. Lopez-Ribot. 2001. Biofilms of Candida albicans and their associated resistance to antifungal agents. Am. Clin. Lab. 20:4244.
87. Saville, S. P.,, A. L. Lazzell,, C. Monteagudo, and, J. L. Lopez-Ribot. 2003. Engineered control of cell morphology in vivo reveals distinct roles for yeast and filamentous forms of Candida albicans during infection. Eukaryot. Cell 2:10531060.
88. Sbarbati, A.,, V. Fanos,, P. Bernardi, and, L. Tato. 2001. Rapid diagnosis of fungal infection of intravascular catheters in newborns by scanning electron microscopy. Scanning 23:376378.
89. Schinabeck, M. K.,, L. A. Long,, M. A. Hossain,, J. Chandra,, P. K. Mukherjee,, S. Mohamed, and, M. A. Ghannoum. 2004. Rabbit model of Candida albicans biofilm infection: liposomal amphotericin B antifungal lock therapy. Antimicrob. Agents Chemother. 48:17271732.
90. Sheehan, D. J.,, C. A. Hitchcock, and, C. M. Sibley. 1999. Current and emerging azole antifungal agents. Clin. Microbiol. Rev. 12:4079.
91. Suci, P. A.,, G. G. Geesey, and, B. J. Tyler. 2001. Integration of Raman microscopy, differential interference contrast microscopy, and attenuated total reflection Fourier transform infrared spectroscopy to investigate chlorhexidine spatial and temporal distribution in Candida albicans biofilms. J. Microbiol. Methods 46:193208.
92. Tripathi, G.,, C. Wiltshire,, S. Macaskill,, H. Tournu,, S. Budge, and, A. J. Brown. 2002. Gcn4 co-ordinates morphogenetic and metabolic responses to amino acid starvation in Candida albicans. EMBO J. 21:54485456.
93. Viudes, A.,, J. Peman,, E. Canton,, P. Ubeda,, J. L. Lopez-Ribot, and, M. Gobernado. 2002. Candidemia at a tertiary-care hospital: epidemiology, treatment, clinical outcome and risk factors for death. Eur. J. Clin. Microbiol. Infect. Dis. 21:767774.
94. Wey, S. B.,, M. Mori,, M. A. Pfaller,, R. F. Woolson, and, R. P. Wenzel. 1988. Hospital-acquired candidemia. The attributable mortality and excess length of stay. Arch. Intern. Med. 148:26422645.
95. White, T. C.,, K. A. Marr, and, R. A. Bowden. 1998. Clinical, cellular, and molecular factors that contribute to antifungal drug resistance. Clin. Microbiol. Rev. 11:382402.
96. Wiederhold, N. P.,, R. E. Lewis,, M. D. Johnson, and, J. R. Perfect. 2003. The echinocandin antifungals: an overview of the pharmacology, spectrum and clinical efficacy. Caspofungin: first approved agent in a new class of anti-fungals. Expert Opin. Investig. Drugs 12:13131333.
97. Wilson, L. S.,, C. M. Reyes,, M. Stolpman,, J. Speckman,, K. Allen, and, J. Beney. 2002. The direct cost and incidence of systemic fungal infections. Value Health 5:2634.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error