Clinical breakpoints for voriconazole and Candida spp. revisited: Review of microbiologic, molecular, pharmacodynamic, and clinical data as they pertain to the development of species-specific interpretive criteria

Diagnostic Microbiology and Infectious Disease

Volumn 70, Issue 3, 2011, Pages 330-343

  Pfaller, Michael A ^a   Andes, David ^b   Arendrup, Maiken C ^c   Diekema, Daniel J ^a   Espinel Ingroff, Ana ^d   Alexander, Barbara D ^e   Brown, Steven D ^f   Chaturvedi, Vishnu ^g   Fowler, Cynthia L ^h   Ghannoum, Mahmoud A ⁱ   Johnson, Elizabeth M ^j   Knapp, Cynthia C ^k   Motyl, Mary R ^l   Ostrosky Zeichner, Luis ^m   Walsh, Thomas J ⁿ  

^a UNIVERSITY OF IOWA   (United States)

^b UNIVERSITY OF WISCONSIN MADISON   (United States)

^c STATENS SERUM INSTITUT   (Denmark)

^d VIRGINIA COMMONWEALTH UNIVERSITY MEDICAL CENTER   (United States)

^e DUKE UNIVERSITY   (United States)

^f CLINICAL MICROBIOLOGY INSTITUTE   (United States)

^g NEW YORK STATE DEPARTMENT OF HEALTH   (United States)

^h BIOMÉRIEUX   (France)

ⁱ CASE WESTERN RESERVE UNIVERSITY   (United States)

^j HPA Centre for Infections   (United Kingdom)

^k Trek Diagnostic Systems   (United States)

^l MERCK RESEARCH LABORATORIES   (United States)

^m UNIVERSITY OF TEXAS MEDICAL SCHOOL   (United States)

ⁿ WEILL CORNELL MEDICAL COLLEGE   (United States)

more..

Author keywords

Candida; Voriconazole breakpoints

Indexed keywords

CANDIDA DRUG RESISTANCE PROTEIN; ERG11 PROTEIN; FLUCONAZOLE; FUNGAL PROTEIN; ITRACONAZOLE; POSACONAZOLE; UNCLASSIFIED DRUG; VORICONAZOLE;

ANTIFUNGAL RESISTANCE; ANTIFUNGAL SUSCEPTIBILITY; ARTICLE; BROTH DILUTION; CANDIDA; CANDIDA ALBICANS; CANDIDA DRUG RESISTANCE GENE; CANDIDA GLABRATA; CANDIDA KRUSEI; CANDIDA PARAPSILOSIS; CANDIDA TROPICALIS; CANDIDIASIS; CLAVISPORA LUSITANIAE; CLINICAL BREAKPOINT; CROSS RESISTANCE; DISK DIFFUSION; ERG11 GENE; FUNGAL GENE; FUNGAL STRAIN; GENE MUTATION; HUMAN; KLUYVEROMYCES MARXIANUS; MICROBIOLOGICAL PARAMETERS; MINIMUM INHIBITORY CONCENTRATION; NONHUMAN; PICHIA GUILLIERMONDII; PRIORITY JOURNAL; PROGNOSIS; SPECIES DIFFERENCE;

ANTIFUNGAL AGENTS; CANDIDA; CANDIDIASIS; HUMANS; MICROBIAL SENSITIVITY TESTS; PYRIMIDINES; TRIAZOLES;

EID: 79959193758     PISSN: 07328893     EISSN: 18790070     Source Type: Journal    
DOI: 10.1016/j.diagmicrobio.2011.03.002     Document Type: Article

References (73)

1. Alexander B.D., Schell W.A., Miller J.L., Long G.D., Perfect J.R. Candida glabrata fungemia in transplant patients receiving voriconazole after fluconazole. Transplantation 2005, 80:868-871.
2. Ally R., Schurmann D., Kreisel W., Carosi G., Aquirrebenogoa A., Dupont B. A randomized, double-blind, double-dummy, multicenter trial of voriconazole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients. Clin. Infect. Dis. 2001, 33:1447-1454.
3. Andes D., Marchillo K., Stamstad T., Conklin R. In vivo pharmacokinetics and pharmacodynamics of a new triazole, voriconazole, in a murine candidiasis model. Antimicrob. Agents Chemother. 2003, 47:3165-3169.
4. Arendrup M.C., Denning D.W. Does one voriconazole breakpoint suit all Candida species?. J. Clin. Microbiol. 2007, 45:2093-2094.
5. Arendrup M.C., Kahlmeter G., Rodriguez-Tudela J.L., Donnelly J.P. Breakpoints for susceptibility testing should not divide wild-type distributions of important target species. Antimicrob. Agents Chemother. 2009, 53:1628-1629.
6. Arthington-Skaggs B.A., Lee-Yang W., Ciblak M.A., Frade J.P., Brandt M.E., Hajjeh R.A., Harrison L.H., Sofair A.N., Warnock D.W. Comparison of visual and spectrophotometric methods of broth microdilution MIC endpoint determinations and evaluation of a sterol quantitation method for in vitro susceptibility testing of fluconazole and itraconazole against trailing and nontrailing Candida isolates. Antimicrob. Agents Chemother. 2002, 46:2477-2481. for the Candidemia Active Surveillance Group.
7. Borst A., Raimer M.T., Warnock D.W., Morrison C.J., Arthington-Skaggs B.A. Rapid acquisition of stable azole resistance by Candida glabrata isolates obtained before the clinical introduction of fluconazole. Antimicrob. Agents Chemother. 2005, 49:783-787.
8. Chandrasekar P.H., Manavathu E. Voriconazole: a second generation triazole. Drugs Today 2001, 37:135-148.
9. Chau A.S., Mendrick C.A., Sabatelli F.J., Loebenberg D., McNicholas P. Application of real-time quantitative PCR to molecular analysis of Candida albicans strains exhibiting reduced susceptibility to azoles. Antimicrob. Agents Chemother. 2004, 48:2124-2131.
10. Chen A., Sobel J.D. Emerging azole antifungals. Expert. Opin. Emerg. Drugs 2005, 10:21-33.
11. Chryssanthou E., Cuenca-Estrella M. Comparison of the Antifungal Susceptibility Testing Subcommittee of the European Committee on Antibiotic Susceptibility Testing Proposed Standard and the E-test with the NCCLS broth microdilution method for voriconazole and caspofungin susceptibility testing of yeast species. J. Clin. Microbiol. 2002, 40:3841-3844.
12. Clinical and Laboratory Standards Institute (CLSI) Reference method for broth dilution antifungal susceptibility testing of yeasts: Approved standard-3rd ed, M27-A3 2008, CLSI, Wayne, PA.
13. Clinical and Laboratory Standards Institute (CLSI) Reference method for broth dilution antifungal susceptibility testing of yeasts: 3rd informational supplement, M27-S3 2008, CLSI, Wayne, PA.
14. Clinical and Laboratory Standards Institute (CLSI) Method for antifungal disk diffusion susceptibility testing of yeasts: Approved standard M44-A2 2008, CLSI, Wayne, PA.
15. Cuenca-Estrella M., Diaz-Guerra T.M., Mellado E., Monzon A., Rodriguez-Tudela J.L. Comparative in vitro activity of voriconazole and itraconazole against fluconazole-susceptible and fluconazole-resistant clinical isolates of Candida species from Spain. Eur. J. Clin. Microbiol. Infect. Dis. 1999, 18:432-435.
16. Diekema D.J., Messer S.A., Hollis R.J., Boyken L., Tendolkar S., Kroeger J., Jones R.N., Pfaller M.A. A global evaluation of voriconazole activity tested against recent clinical isolates of Candida spp. Diagn. Microbiol. Infect. Dis. 2009, 63:233-236.
17. Espinel-Ingroff A., Barchiesi F., Cuenca-Estrella M., Fothergill A., Pfaller M.A., Rinaldi M., Rodriguez-Tudela J.L., Verweij P.E. Comparison of visual 24-hour and spectrophotometric 48-hour MICs to CLSI reference microdilution MICs of fluconazole, itraconazole, posaconazole, and voriconazole for Candida spp.: a collaborative study. J. Clin. Microbiol. 2005, 43:4535-4540.
18. Espinel-Ingroff A., Barchiesi F., Cuenca-Estrella M., Pfaller M.A., Rinaldi M., Rodriguez-Tudela J.L., Verweij P.E. International and multicenter comparison of EUCAST and CLSI M27-A2 broth microdilution methods for testing susceptibilities of Candida spp. to fluconazole, itraconazole, posaconazole, and voriconazole. J. Clin. Microbiol. 2005, 43:3884-3889.
19. Espinel-Ingroff A., Canton E., Peman J., Rinaldi M.G., Fothergill A.W. Comparison of 24-hour and 48-hour voriconazole MICs as determined by the Clinical and Laboratory Standards Institute broth microdilution method (M27-A3 document) in three laboratories: results obtained with 2,162 clinical isolates of Candida spp. and other yeasts. J. Clin. Microiol. 2009, 47:2766-2771.
20. EUCAST EUCAST technical note on voriconazole. Clin. Microbiol. Infect. 2008, 14:985-987.
21. EUCAST Voriconazole: rationale for the clinical breakpoints, version 2.0. Available at: http://www.eucast.org.
22. Garey K.W., Rege M., Pai M.P., Mingo D.E., Sada K.J., Turpin R.S., Bearden D.T. Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin. Infect. Dis. 2006, 43:25-31.
23. Herbrecht R., Denning D.W., Patterson T.F., Bennett J.E., Greene R.E., Oestmann J.W., Kern W.V., Marr K.A., Ribaud P., Lortholary O., Sylvester R., Rubin R.H., Wingard J.R., Stark P., Durand C., Caillot D., Thiel E., Chandrasekar P.H., Hodges M.R., Schlamm H.T., Troke P.F., de Pauw B. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N. Engl. J. Med. 2002, 347:408-415. Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group.
24. Imhof A., Balajee A., Fredricks D., England J., Marr K.A. Breakthrough fungal infections in stem cell transplant recipients receiving voriconazole. Clin. Infect. Dis. 2004, 39:743-746.
25. Johnson E., Espinel-Ingroff A., Szekely A., Hockey H., Troke P. Activity of voriconazole, itraconazole, fluconazole and amphotericin B in vitro against 1763 yeasts from 472 patients in the voriconazole phase III clinical studies. Int. J. Antimicrob. Agents 2008, 32:511-514.
26. Kahlmeter G., Brown D.F.J., Goldstein F.W., McGowan A.P., Mouton J.W., Osterlund A., Rodloff A., Steinbakk M., Urbaskova P., Vatopoulos A. European harmonization of MIC breakpoints for antimicrobial susceptibility testing of bacteria. J. Antimicrob. Chemother. 2003, 52:145-148.
27. Kahlmeter G., Brown D.F.J. Harmonization of antimicrobial breakpoints in Europe - can it be achieved?. Clin. Microbiol. Newsl. 2004, 26:187-192.
28. Kullberg B.J., Sobel J.D., Ruhnke M., Pappas P.G., Viscoli C., Rex J.H., Cleary J.D., Rubinstein E., Church L.W., Brown J.M., Schlamm H.T., Oborsha I.T., Hilton F., Hodges M.R. Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidemia in non-netropenic patients: a randomized non-inferiority trial. Lancet 2005, 366:1435-1442.
29. Lopez-Ribot J.L., McAtee R.K., Pera S., Kirkpatrick W.R., Rinaldi M.G., Patterson T.F. Multiple resistant phenotypes of Candida albicans coexist during episodes of oropharyngeal candidiasis in human immunodeficiency virus-infected patients. Antimicrob. Agents Chemother. 1999, 43:1621-1630.
30. MacCallum D.M., Coste A., Ischer F., Jacobson M.D., Odds F.C., Sanglard D. Genetic dissection of azole resistance mechanisms in Candida albicans and their validation in a mouse model of disseminated infection. Antimicrob. Agents Chemother. 2010, 54:1476-1483.
31. Magill S.S., Shields C., Sears C.L., Choti M., Merz W.G. Triazole cross-resistance among Candida spp.: case report, occurrence among bloodstream isolates, and implication for antifungal therapy. J. Clin. Microbiol. 2006, 44:529-535.
32. Marr K.A., White T.C., van Burik J.A., Bowden R.A. Development of fluconazole resistance in Candida albicans causing disseminated infection in a patient undergoing marrow transplantation. Clin. Infect. Dis. 1997, 25:908-910.
33. Metzler C.M., DeHaan R.M. Susceptibility tests of anaerobic bacteria: statistical and clinical considerations. J. Infect. Dis. 1974, 130:588-594.
34. Mori T., Matsumura M., Kanamaru Y., Miyano S., Hishikawa T., Irie S., Oshimi K., Saikawa T., Oguri T. Myelofibrosis complicated by infection due to Candida albicans: emergence of resistance to antifungal agents during therapy. Clin. Infect. Dis. 1997, 25:1470-1471.
35. Morrell M., Fraser V.J., Kollef M.H. Delaying empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for mortality. Antimicrob. Agents Chemother. 2005, 49:3640-3645.
36. Moudgal V., Little T., Baikov D., Vazquez J.A. Multiechinocandin- and multitriazole-resistant Candida parapsilosis isolates serially obtained during therapy for prosthetic valve endocarditis. Antimicrob. Agents Chemother. 2005, 49:767-769.
37. Ostrosky-Zeichner L., Rex J.H., Pappas P.G., Hamill R.J., Larsen R.A., Horowitz H.W., Powderly W.G., Hyslop N., Kauffman C.A., Cleary J., Manino J.E., Lee J. Antifungal susceptibility survey of 2,000 bloodstream Candida isolates in the United States. Antimicrob. Agents Chemother. 2003, 47:3149-3154.
38. Ostrosky-Zeichner L., Rex J.H., Pfaller M.A., Diekema D.J., Alexander B.D., Andes D., Brown S.D., Chaturvedi V., Ghannoum M.A., Knapp C.C., Sheehan D.J., Walsh T.J. Rationale for reading fluconazole MICs at 24 hours rather than 48 hours when testing Candida spp. by the CLSI M27-A2 standard method. Antimicrob. Agents Chemother. 2008, 52:4175-4177.
39. Oxman D.A., Chow J.K., Frendlt G., Hadley S., Hershkovitz S., Ireland P., McDermott L.A., Tsai K., Marty F.M., Kontoyiannis D.P., Golan Y. Candidemia associated with decreased in vitro fluconazole susceptibility: Is Candida speciation predictive of the susceptibility pattern?. J. Antimicrob. Chemother. 2010, 65:1460-1465.
40. Panckal A.A., Gribskov J.L., Staab J.F., Kirby K.A., Rinaldi M., Marr K.A. Clinical significance of azole antifungal drug cross-resistance in Candida glabrata. J. Clin. Microbiol. 2006, 44:1740-1743.
41. Pappas P.G., Kauffman C.A., Andes D., Benjamin D.K., Candalara T.F., Edwards J.E., Filler S.G., Fisher J.F., Kullberg B.J., Ostrosky-Zeichner L., Reboli A.C., Rex J.H., Walsh T.J., Sobel J.D. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin. Infect. Dis. 2009, 48:503-535.
42. Parkins M.D., Sabuda D.M., Elsayed S., Laupland K.B. Adequacy of empirical antifungal therapy and effect on outcome among patients with invasive Candida species infections. J. Antimicrob. Chemother. 2007, 60:613-618.
43. Perfect J.R., Marr K.A., Walsh T.J., Greenberg R.N., DuPont B., dela Torre-Cisneros J., Just-Nubling G., Schlamm H.T., Lutsar I., Espinel-Ingroff A., Johnson E. Voriconazole treatment for less-common, emerging or refractory fungal infections. Clin. Infect. Dis. 2003, 36:1122-1131.
44. Pfaller M.A., Messer S.A., Hollis R.J., Jones R.N., Diekema D.J. In vitro activities of ravuconazole and voriconazole compared with those of four approved systemic antifungal agents against 6,970 clinical isolates of Candida spp. Antimicrob. Agents Chemother. 2002, 46:1723-1727.
45. Pfaller M.A., Diekema D.J. Rare and emerging opportunistic fungal pathogens: concerns for resistance beyond Candida albicans and Aspergillus fumigatus. J. Clin. Microbiol. 2004, 42:4419-4431.
46. Pfaller M.A., Boyken L., Messer S.A., Tendolkar S., Hollis R.J., Diekema D.J. Comparison of results of voriconazole disk diffusion testing for Candida species with results from a central reference laboratory in the ARTEMIS Global Antifungal Surveillance Program. J. Clin. Microbiol. 2005, 43:5208-5213.
47. Pfaller M.A., Diekema D.J., Rex J.H., Espinel-Ingroff A., Johnson E.M., Andes D., Chaturvedi V., Ghannoum M.A., Odds F.C., Rinaldi M.G., Sheehan D.J., Troke P., Walsh T.J., Warnock D.W. Correlation of MIC with outcome for Candida species tested against voriconazole: analysis and proposal for interpretive breakpoints. J. Clin. Microbiol. 2006, 44:819-826.
48. Pfaller M.A., Diekema D.J. Azole antifungal drug cross-resistance: mechanisms, epidemiology, and clinical significance. J. Invasive. Fungal. Infect. 2007, 1:74-92.
49. Pfaller M.A., Messer S.A., Boyken L., Hollis R.J., Tendolkar S., Diekema D.J. Use of fluconazole as a surrogate marker to predict susceptibility and resistance to voriconazole among 13,338 clinical isolates of Candida spp. tested by Clinical and Laboratory Standards Institute - recommended broth microdilution methods. J. Clin. Microbiol. 2007, 45:70-75.
50. Pfaller M.A., Boyken L.B., Hollis R.J., Kroeger J., Messer S.A., Tendolkar S., Diekema D.J. Validation of 24-hour fluconazole MIC readings versus the CLSI 48-hour broth microdilution reference method: results from a Global Candida Antifungal Surveillance Program. J. Clin. Microbiol. 2008, 46:3585-3590.
51. Pfaller M.A., Boyken L., Hollis R.J., Kroeger J., Messer S.A., Tendolkar S., Diekema D.J. Comparison of results of fluconazole and voriconazole disk diffusion testing for Candida spp. with results from a central reference laboratory in the ARTEMIS DISK Global Antifungal Surveillance Program. Diagn. Microbiol. Infect. Dis. 2009, 65:27-34. The ARTEMIS DISK Global Antifungal Surveillance Group.
52. Pfaller M.A., Diekema D.J. Wild-type MIC distributions and epidemiological cutoff values for fluconazole and Candida: time for new clinical breakpoints?. Curr. Fungal. Infect. Reports. 2010, 4:168-174.
53. Pfaller M.A., Diekema D.J., Gibbs D.L., Newell V.A., Ellis D., Tullio V., Rodloff A., Fu W., Ling T.A. Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: a 10.5-year analysis of susceptibilities of Candida species to fluconazole and voriconazole as determined by CLSI standardized disk diffusion. J. Clin. Microbiol. 2010, 48:1366-1372. The Global Antifungal Surveillance Group.
54. Pfaller M.A., Andes D., Diekema D.J., Espinel-Ingroff A., Sheehan D. Wild-type MIC distributions, epidemiological cutoff values and species-specific clinical breakpoints for fluconazole and Candida: time for harmonization of CLSI and EUCAST broth microdilution methods. Drug. Resist. Updates. 2010, 13:180-195. The CLSI Subcommittee for Antifungal Testing.
55. Pfaller M.A., Boyken L., Hollis R.J., Kroeger J., Messer S.A., Tendolkar S., Jones R.N., Turnidge J., Diekema D.J. Wild-type MIC distributions and epidemiological cutoff values for the echinocandins and Candida spp. J. Clin. Microbiol. 2010, 48:52-56.
56. Pfaller M.A., Espinel-Ingroff A., Boyken A., Hollis R.J., Kroeger J., Messer S.A., Tendolkar S., Diekema D.J. Comparison of the broth microdilution (BMD) method of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) with the 24-h CLSI BMD method for fluconazole, posaconazole, and voriconazole susceptibility testing of Candida species using epidemiological cutoff values. J. Clin. Microbiol. 2011, 49:845-850.
57. Pfaller M.A., Boyken L., Hollis R.J., Kroeger J., Messer S.A., Tendolkar S., Diekema D.J. Wild-type MIC distributions and epidemiological cutoff values for posaconazole and voriconazole and Candida spp. as determined by 24-h CLSI broth microdilution methods. J. Clin. Microbiol. 2011, 49:630-637.
58. Pfaller M.A., Boyken L.B., Hollis R.J., Kroeger J., Messer S.A., Tendolkar S., Diekema D.J. Validation of 24-hour posaconazole and voriconazole MIC readings versus the CLSI 48-hour broth microdilution reference method: application of epidemiological cutoff values to results from a global Candida antifungal surveillance program. J. Clin. Microbiol. 2011, 49:1274-1279.
59. Posteraro B., Tumbarello M., La Sorda M., Spanu T., Trecarichi E.M., De Bernardis F., Scoppettuolo G., Sanguinetti M., Fadda G. Azole resistance of Candida glabrata in a case of recurrent fungemia. J. Clin. Microbiol. 2006, 44:3046-3047.
60. Revankar S.G., Kirkpatrick W.R., McAtee R.K., Fothergill A.W., Redding S.W., Rinaldi M.G., Patterson T.F. Interpretation of trailing endpoints in antifungal susceptibility testing by the National Committee for Clinical Laboratory Standards method. J. Clin. Microbiol. 1998, 36:153-156.
61. Rex J.H., Nelson P.W., Paetznick V.L., Lozano-Chiu M., Espinel-Ingroff A., Anaissie E.J. Optimizing the correlation between results of testing in vitro and therapeutic outcome in vivo for fluconazole by testing critical isolates in a murine model of invasive candidiasis. Antimicrob. Agents Chemother. 1998, 42:129-134.
62. Rex J.H., Pfaller M.A. Has antifungal susceptibility testing come of age?. Clin. Infect. Dis. 2002, 35:982-989.
63. Sabatelli F., Patel R., Mann P.A., Mendrick C.A., Norris C.C., Hare R., Loebenberg D., Black T.A., McNicholas P.M. In vitro activity of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts. Antimicrob. Agents Chemother. 2006, 50:2009-2015.
64. Sanglard D., Kuehler K., Ischer F., Pagami J.L., 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, 39:2378-2386.
65. 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, 40:2300-2305.
66. 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 1996, 143:405-416.
67. Sanglard D., Odds F.C. Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences. Lancet Infect. Dis. 2002, 2:73-85.
68. 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, 48:668-679.
69. Simjee S., Silley P., Werling H.O., Bywater R. Potential confusion regarding the term "resistance" in epidemiological surveys. J. Antimicrob. Chemother. 2008, 61:228-229.
70. Turnidge J., Kahlmeter G., Krovall G. Statistical characterization of bacterial wild-type MIC value distributions and determinations of epidemiological cut-off values. Clin. Microbiol. Infect. 2006, 12:418-425.
71. Turnidge J., Paterson D.L. Setting and revising antibacterial susceptibility breakpoints. Clin. Microbiol. Rev. 2007, 20:391-408.
72. Walsh T.J., Pappas P., Winston D.J., Lazarus H.M., Petersen F., Raffalli J. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N. Engl. J. Med. 2002, 346:225-234.
73. White T.C. The presence of an R467K amino acid substitution and loss of allelic variation correlate with an azole- resistant lanosterol 14 α-demethylase in Candida albicans. Antimicrob. Agents Chemother. 1997, 41:1488-1494.