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Semin Respir Crit Care Med 2008; 29(2): 198-210
DOI: 10.1055/s-2008-1063858
Published by Thieme Medical Publishers

Update on Azole Antifungals

Dimitrios I. Zonios1 , John E. Bennett1
  • 1Clinical Mycology Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, Maryland
Further Information

Publication History

Publication Date:
26 March 2008 (online)

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ABSTRACT

This is a comprehensive, clinically oriented review of the four commercially available triazoles: fluconazole, itraconazole, voriconazole, and posaconazole. Emphasis is placed in pharmacology, drug interactions, adverse events, antifungal activity, and the evolving perspective of their clinical use. Key clinical trials are briefly discussed, and specific drug indications summarized. Fluconazole remains a valuable low-cost choice for the treatment of various fungal infections, including candidiasis and cryptococcosis. It has relatively few drug interactions and is safe but lacks activity against filamentous fungi. The use of itraconazole is historically plagued by erratic bioavailability of the oral capsule, improved with the oral solution. Drug interactions are numerous. Itraconazole exhibits significant activity against Aspergillus and the endemic fungi. Voriconazole has revolutionized the treatment of aspergillosis in severely immunocompromised patients, but its use is compromised by complicated pharmacokinetics, notable drug interactions, and relatively significant adverse events. Finally, posaconazole is the last addition to the azole armamentarium with extended antifungal spectrum, significant activity against the zygomycetes, and, apparently, optimal safety profile. Posaconazole has a significant role for the prophylaxis of invasive fungal infections in severely immunocompromised patients. Multiple daily dosing, a need for fatty foods for absorption, and absence of an intravenous formulation restrict its use to selected populations.

KEYWORDS

Azoles - triazoles - fluconazole - itraconazole - voriconazole - posaconazole - azole interactions

REFERENCES

  • 1 Brammer K W, Farrow P R, Faulkner J K. Pharmacokinetics and tissue penetration of fluconazole in humans.  Rev Infect Dis. 1990;  12(Suppl 3) S318-S326
    PubMedGoogle Scholar
  • 2 Barone J A, Moskovitz B L, Guarnieri J et al.. Food interaction and steady-state pharmacokinetics of itraconazole oral solution in healthy volunteers.  Pharmacotherapy. 1998;  18 295-301
    PubMedGoogle Scholar
  • 3 Barone J A, Moskovitz B L, Guarnieri J et al.. Enhanced bioavailability of itraconazole in hydroxypropyl-beta-cyclodextrin solution versus capsules in healthy volunteers.  Antimicrob Agents Chemother. 1998;  42 1862-1865
    PubMedGoogle Scholar
  • 4 Kintzel P E, Rollins C J, Yee W J, List A F. Low itraconazole serum concentrations following administration of itraconazole suspension to critically ill allogeneic bone marrow transplant recipients.  Ann Pharmacother. 1995;  29 140-143
    PubMedGoogle Scholar
  • 5 Hyland R, Jones B C, Smith D A. Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole.  Drug Metab Dispos. 2003;  31 540-547
    CrossrefPubMedGoogle Scholar
  • 6 Hariprasad S M, Mieler W F, Holz E R et al.. Determination of vitreous, aqueous, and plasma concentration of orally administered voriconazole in humans.  Arch Ophthalmol. 2004;  122 42-47
    CrossrefPubMedGoogle Scholar
  • 7 Roffey S J, Cole S, Comby P et al.. The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human.  Drug Metab Dispos. 2003;  31 731-741
    CrossrefPubMedGoogle Scholar
  • 8 Boyd A E, Modi S, Howard S J, Moore C B, Keevil B G, Denning D W. Adverse reactions to voriconazole.  Clin Infect Dis. 2004;  39 1241-1244
    CrossrefPubMedGoogle Scholar
  • 9 Tan K, Brayshaw N, Tomaszewski K, Troke P, Wood N. Investigation of the potential relationships between plasma voriconazole concentrations and visual adverse events or liver function test abnormalities.  J Clin Pharmacol. 2006;  46 235-243
    CrossrefPubMedGoogle Scholar
  • 10 Imhof A, Schaer D J, Schanz U, Schwarz U. Neurological adverse events to voriconazole: evidence for therapeutic drug monitoring.  Swiss Med Wkly. 2006;  136 739-742
    PubMedGoogle Scholar
  • 11 Smith J, Safdar N, Knasinski V et al.. Voriconazole therapeutic drug monitoring.  Antimicrob Agents Chemother. 2006;  50 1570-1572
    CrossrefPubMedGoogle Scholar
  • 12 Trifilio S, Pennick G, Pi J et al.. Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients.  Cancer. 2007;  109 1532-1535
    CrossrefPubMedGoogle Scholar
  • 13 Ikeda Y, Umemura K, Kondo K, Sekiguchi K, Miyoshi S, Nakashima M. Pharmacokinetics of voriconazole and cytochrome P450 2C19 genetic status.  Clin Pharmacol Ther. 2004;  75 587-588
    CrossrefPubMedGoogle Scholar
  • 14 Mizutani T. PM frequencies of major CYPs in Asians and Caucasians.  Drug Metab Rev. 2003;  35 99-106
    PubMedGoogle Scholar
  • 15 Courtney R, Wexler D, Radwanski E, Lim J, Laughlin M. Effect of food on the relative bioavailability of two oral formulations of posaconazole in healthy adults.  Br J Clin Pharmacol. 2004;  57 218-222
    CrossrefPubMedGoogle Scholar
  • 16 Ezzet F, Wexler D, Courtney R, Krishna G, Lim J, Laughlin M. Oral bioavailability of posaconazole in fasted healthy subjects: comparison between three regimens and basis for clinical dosage recommendations.  Clin Pharmacokinet. 2005;  44 211-220
    CrossrefPubMedGoogle Scholar
  • 17 Ullmann A J, Cornely O A, Burchardt A et al.. Pharmacokinetics, safety, and efficacy of posaconazole in patients with persistent febrile neutropenia or refractory invasive fungal infection.  Antimicrob Agents Chemother. 2006;  50 658-666
    CrossrefPubMedGoogle Scholar
  • 18 Wexler D, Courtney R, Richards W, Banfield C, Lim J, Laughlin M. Effect of posaconazole on cytochrome P450 enzymes: a randomized, open-label, two-way crossover study.  Eur J Pharm Sci. 2004;  21 645-653
    CrossrefPubMedGoogle Scholar
  • 19 Palkama V J, Isohanni M H, Neuvonen P J, Olkkola K T. The effect of intravenous and oral fluconazole on the pharmacokinetics and pharmacodynamics of intravenous alfentanil.  Anesth Analg. 1998;  87 190-194
    CrossrefPubMedGoogle Scholar
  • 20 Saari T I, Laine K, Leino K, Valtonen M, Neuvonen P J, Olkkola K T. Voriconazole, but not terbinafine, markedly reduces alfentanil clearance and prolongs its half-life.  Clin Pharmacol Ther. 2006;  80 502-508
    CrossrefPubMedGoogle Scholar
  • 21 Lefebvre R A, Van Peer A, Woestenborghs R. Influence of itraconazole on the pharmacokinetics and electrocardiographic effects of astemizole.  Br J Clin Pharmacol. 1997;  43 319-322
    CrossrefPubMedGoogle Scholar
  • 22 Kivisto K T, Lamberg T S, Kantola T, Neuvonen P J. Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole.  Clin Pharmacol Ther. 1997;  62 348-354
    CrossrefPubMedGoogle Scholar
  • 23 Buggia I, Zecca M, Alessandrino E P et al.. Itraconazole can increase systemic exposure to busulfan in patients given bone marrow transplantation. GITMO (Gruppo Italiano Trapianto di Midollo Osseo).  Anticancer Res. 1996;  16 2083-2088
    PubMedGoogle Scholar
  • 24 Nair D R, Morris H H. Potential fluconazole-induced carbamazepine toxicity.  Ann Pharmacother. 1999;  33 790-792
    PubMedGoogle Scholar
  • 25 Marr K A, Leisenring W, Crippa F et al.. Cyclophosphamide metabolism is affected by azole antifungals.  Blood. 2004;  103 1557-1559
    PubMedGoogle Scholar
  • 26 Osowski C L, Dix S P, Lin L S, Mullins R E, Geller R B, Wingard J R. Evaluation of the drug interaction between intravenous high-dose fluconazole and cyclosporine or tacrolimus in bone marrow transplant patients.  Transplantation. 1996;  61 1268-1272
    CrossrefPubMedGoogle Scholar
  • 27 Lopez-Gil J A. Fluconazole-cyclosporine interaction: a dose-dependent effect?.  Ann Pharmacother. 1993;  27 427-430
    PubMedGoogle Scholar
  • 28 Saad A H, DePestel D D, Carver P L. Factors influencing the magnitude and clinical significance of drug interactions between azole antifungals and select immunosuppressants.  Pharmacotherapy. 2006;  26 1730-1744
    CrossrefPubMedGoogle Scholar
  • 29 Romero A J, Pogamp P L, Nilsson L G, Wood N. Effect of voriconazole on the pharmacokinetics of cyclosporine in renal transplant patients.  Clin Pharmacol Ther. 2002;  71 226-234
    CrossrefPubMedGoogle Scholar
  • 30 Partanen J, Jalava K M, Neuvonen P J. Itraconazole increases serum digoxin concentration.  Pharmacol Toxicol. 1996;  79 274-276
    PubMedGoogle Scholar
  • 31 Courtney R DSP, Laughlin M, Lim J et al.. Effect of posaconazole on the pharmacokinetics of cyclosporine. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, December 16-19, 2001 Washington, DC; American Society for Microbiology 2001: A27
    Google Scholar
  • 32 Purkins L, Wood N, Kleinermans D, Nichols D. Voriconazole does not affect the steady-state pharmacokinetics of digoxin.  Br J Clin Pharmacol. 2003;  56(Suppl 1) 45-50
    CrossrefPubMedGoogle Scholar
  • 33 Jalava K M, Partanen J, Neuvonen P J. Itraconazole decreases renal clearance of digoxin.  Ther Drug Monit. 1997;  19 609-613
    CrossrefPubMedGoogle Scholar
  • 34 Jalava K M, Olkkola K T, Neuvonen P J. Itraconazole greatly increases plasma concentrations and effects of felodipine.  Clin Pharmacol Ther. 1997;  61 410-415
    CrossrefPubMedGoogle Scholar
  • 35 Shimizu M, Uno T, Sugawara K, Tateishi T. Effects of single and multiple doses of itraconazole on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein.  Br J Clin Pharmacol. 2006;  62 372-376
    CrossrefPubMedGoogle Scholar
  • 36 Niemi M, Backman J T, Neuvonen M, Laitila J, Neuvonen P J, Kivisto K T. Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride.  Clin Pharmacol Ther. 2001;  69 194-200
    CrossrefPubMedGoogle Scholar
  • 37 Yasui N, Kondo T, Otani K et al.. Effects of itraconazole on the steady-state plasma concentrations of haloperidol and its reduced metabolite in schizophrenic patients: in vivo evidence of the involvement of CYP3A4 for haloperidol metabolism.  J Clin Psychopharmacol. 1999;  19 149-154
    CrossrefPubMedGoogle Scholar
  • 38 Hynninen V V, Olkkola K T, Leino K et al.. Effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of s-( + )- and R-(-)- Ibuprofen.  Antimicrob Agents Chemother. 2006;  50 1967-1972
    CrossrefPubMedGoogle Scholar
  • 39 Dutreix C, Peng B, Mehring G et al.. Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects.  Cancer Chemother Pharmacol. 2004;  54 290-294
    PubMedGoogle Scholar
  • 40 Kaukonen K M, Olkkola K T, Neuvonen P J. Fluconazole but not itraconazole decreases the metabolism of losartan to E-3174.  Eur J Clin Pharmacol. 1998;  53 445-449
    CrossrefPubMedGoogle Scholar
  • 41 Kivisto K T, Kantola T, Neuvonen P J. Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin.  Br J Clin Pharmacol. 1998;  46 49-53
    CrossrefPubMedGoogle Scholar
  • 42 Tarumi Y, Pereira J, Watanabe S. Methadone and fluconazole: respiratory depression by drug interaction.  J Pain Symptom Manage. 2002;  23 148-153
    CrossrefPubMedGoogle Scholar
  • 43 Liu P, Foster G, Labadie R, Somoza E, Sharma A. Pharmacokinetic interaction between voriconazole and methadone at steady state in patients on methadone therapy.  Antimicrob Agents Chemother. 2007;  51 110-118
    PubMedGoogle Scholar
  • 44 Varis T, Kaukonen K M, Kivisto K T, Neuvonen P J. Plasma concentrations and effects of oral methylprednisolone are considerably increased by itraconazole.  Clin Pharmacol Ther. 1998;  64 363-368
    CrossrefPubMedGoogle Scholar
  • 45 Olkkola K T, Ahonen J, Neuvonen P J. The effects of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam.  Anesth Analg. 1996;  82 511-516
    CrossrefPubMedGoogle Scholar
  • 46 Saari T I, Laine K, Leino K, Valtonen M, Neuvonen P J, Olkkola K T. Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam.  Clin Pharmacol Ther. 2006;  79 362-370
    CrossrefPubMedGoogle Scholar
  • 47 Jaruratanasirikul S, Sriwiriyajan S. Pharmacokinetic study of the interaction between itraconazole and nevirapine.  Eur J Clin Pharmacol. 2007;  63 451-456
    CrossrefPubMedGoogle Scholar
  • 48 Wood N, Tan K, Purkins L et al.. Effect of omeprazole on the steady-state pharmacokinetics of voriconazole.  Br J Clin Pharmacol. 2003;  56(Suppl 1) 56-61
    CrossrefPubMedGoogle Scholar
  • 49 Yasui-Furukori N, Saito M, Niioka T, Inoue Y, Sato Y, Kaneko S. Effect of itraconazole on pharmacokinetics of paroxetine: the role of gut transporters.  Ther Drug Monit. 2007;  29 45-48
    CrossrefPubMedGoogle Scholar
  • 50 Blum R A, Wilton J H, Hilligoss D M et al.. Effect of fluconazole on the disposition of phenytoin.  Clin Pharmacol Ther. 1991;  49 420-425
    PubMedGoogle Scholar
  • 51 Purkins L, Wood N, Ghahramani P, Love E R, Eve M D, Fielding A. Coadministration of voriconazole and phenytoin: pharmacokinetic interaction, safety, and toleration.  Br J Clin Pharmacol. 2003;  56(Suppl 1) 37-44
    CrossrefPubMedGoogle Scholar
  • 52 Ducharme M P, Slaughter R L, Warbasse L H et al.. Itraconazole and hydroxyitraconazole serum concentrations are reduced more than tenfold by phenytoin.  Clin Pharmacol Ther. 1995;  58 617-624
    PubMedGoogle Scholar
  • 53 Krishna G, Sansone-Parsons A, Kantesaria B. Drug interaction assessment following concomitant administration of posaconazole and phenytoin in healthy men.  Curr Med Res Opin. 2007;  23 1415-1422
    CrossrefPubMedGoogle Scholar
  • 54 Kaukonen K M, Olkkola K T, Neuvonen P J. Itraconazole increases plasma concentrations of quinidine.  Clin Pharmacol Ther. 1997;  62 510-517
    CrossrefPubMedGoogle Scholar
  • 55 Trapnell C B, Narang P K, Li R, Lavelle J P. Increased plasma rifabutin levels with concomitant fluconazole therapy in HIV-infected patients.  Ann Intern Med. 1996;  124 573-576
    PubMedGoogle Scholar
  • 56 Krishna G, Parsons A, Kantesaria B, Mant T. Evaluation of the pharmacokinetics of posaconazole and rifabutin following co-administration to healthy men.  Curr Med Res Opin. 2007;  23 545-552
    CrossrefPubMedGoogle Scholar
  • 57 Jung S M, Kim K A, Cho H K et al.. Cytochrome P450 3A inhibitor itraconazole affects plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients.  Clin Pharmacol Ther. 2005;  78 520-528
    CrossrefPubMedGoogle Scholar
  • 58 Koks C H, Crommentuyn K M, Hoetelmans R M et al.. The effect of fluconazole on ritonavir and saquinavir pharmacokinetics in HIV-1-infected individuals.  Br J Clin Pharmacol. 2001;  51 631-635
    CrossrefPubMedGoogle Scholar
  • 59 Pai M P, Allen S. Voriconazole inhibition of tacrolimus metabolism.  Clin Infect Dis. 2003;  36 1089-1091
    PubMedGoogle Scholar
  • 60 Sansone A BD, Bella D, Statkevich P et al.. Effect of posaconazole on the pharmacokinetics of tacrolimus in healthy volunteers. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Illinois, September 14-17, 2003. Washington, DC; American Society for Microbiology 2003: 1603
    Google Scholar
  • 61 Pohjola-Sintonen S S, Vitasoto M, Toivenen L et al.. Itraconazole prevents terfenadine metabolism and increases risk of torsades de pointes ventricular tachycardia.  Eur J Clin Pharmacol. 1993;  45 191-193
    CrossrefPubMedGoogle Scholar
  • 62 Varhe A, Olkkola K T, Neuvonen P J. Effect of fluconazole dose on the extent of fluconazole-triazolam interaction.  Br J Clin Pharmacol. 1996;  42 465-470
    CrossrefPubMedGoogle Scholar
  • 63 Neuvonen P J, Varhe A, Olkkola K T. The effect of ingestion time interval on the interaction between itraconazole and triazolam.  Clin Pharmacol Ther. 1996;  60 326-331
    CrossrefPubMedGoogle Scholar
  • 64 Bermudez M, Fuster J L, Llinares E, Galera A, Gonzalez C. Itraconazole-related increased vincristine neurotoxicity: case report and review of literature.  J Pediatr Hematol Oncol. 2005;  27 389-392
    CrossrefPubMedGoogle Scholar
  • 65 Mantadakis E, Amoiridis G, Kondi A, Kalmanti M. Possible increase of the neurotoxicity of vincristine by the concurrent use of posaconazole in a young adult with leukemia.  J Pediatr Hematol Oncol. 2007;  29 130
    CrossrefPubMedGoogle Scholar
  • 66 Bosque E. Possible drug interaction between itraconazole and vinorelbine tartrate leading to death after one dose of chemotherapy.  Ann Intern Med. 2001;  134 427
    PubMedGoogle Scholar
  • 67 Black D J, Kunze K L, Wienkers L C et al.. Warfarin-fluconazole, II: A metabolically based drug interaction: in vivo studies.  Drug Metab Dispos. 1996;  24 422-428
    PubMedGoogle Scholar
  • 68 Purkins L, Wood N, Kleinermans D, Nichols D. Voriconazole potentiates warfarin-induced prothrombin time prolongation.  Br J Clin Pharmacol. 2003;  56(Suppl 1) 24-29
    CrossrefPubMedGoogle Scholar
  • 69 Yeh J, Soo S C, Summerton C, Richardson C. Potentiation of action of warfarin by itraconazole.  BMJ. 1990;  301 669
    PubMedGoogle Scholar
  • 70 Sahai J, Gallicano K, Pakuts A, Cameron D W. Effect of fluconazole on zidovudine pharmacokinetics in patients infected with human immunodeficiency virus.  J Infect Dis. 1994;  169 1103-1107
    CrossrefPubMedGoogle Scholar
  • 71 Greenblatt D J, von Moltke L L, Harmatz J S et al.. Kinetic and dynamic interaction study of zolpidem with ketoconazole, itraconazole, and fluconazole.  Clin Pharmacol Ther. 1998;  64 661-671
    CrossrefPubMedGoogle Scholar
  • 72 Saari T I, Laine K, Leino K, Valtonen M, Neuvonen P J, Olkkola K T. Effect of voriconazole on the pharmacokinetics and pharmacodynamics of zolpidem in healthy subjects.  Br J Clin Pharmacol. 2007;  63 116-120
    CrossrefPubMedGoogle Scholar
  • 73 Courtney R, Radwanski E, Lim J, Laughlin M. Pharmacokinetics of posaconazole coadministered with antacid in fasting or nonfasting healthy men.  Antimicrob Agents Chemother. 2004;  48 804-808
    CrossrefPubMedGoogle Scholar
  • 74 May D B, Drew R H, Yedinak K C, Bartlett J A. Effect of simultaneous didanosine administration on itraconazole absorption in healthy volunteers.  Pharmacotherapy. 1994;  14 509-513
    PubMedGoogle Scholar
  • 75 Penzak S R, Gubbins P O, Gurley B J, Wang P L, Saccente M. Grapefruit juice decreases the systemic availability of itraconazole capsules in healthy volunteers.  Ther Drug Monit. 1999;  21 304-309
    CrossrefPubMedGoogle Scholar
  • 76 Purkins L, Wood N, Kleinermans D, Nichols D. Histamine H2-receptor antagonists have no clinically significant effect on the steady-state pharmacokinetics of voriconazole.  Br J Clin Pharmacol. 2003;  56(Suppl 1) 51-55
    CrossrefPubMedGoogle Scholar
  • 77 Lim S G, Sawyerr A M, Hudson M, Sercombe J, Pounder R E. Short report: the absorption of fluconazole and itraconazole under conditions of low intragastric acidity.  Aliment Pharmacol Ther. 1993;  7 317-321
    PubMedGoogle Scholar
  • 78 Jaruratanasirikul S, Sriwiriyajan S. Effect of omeprazole on the pharmacokinetics of itraconazole.  Eur J Clin Pharmacol. 1998;  54 159-161
    CrossrefPubMedGoogle Scholar
  • 79 Panomvana Na Ayudhya D, Thanompuangseree N, Tansuphaswadikul S. Effect of rifampicin on the pharmacokinetics of fluconazole in patients with AIDS.  Clin Pharmacokinet. 2004;  43 725-732
    CrossrefPubMedGoogle Scholar
  • 80 Rengelshausen J, Banfield M, Riedel K D et al.. Opposite effects of short-term and long-term St John's wort intake on voriconazole pharmacokinetics.  Clin Pharmacol Ther. 2005;  78 25-33
    CrossrefPubMedGoogle Scholar
  • 81 Wang E J, Lew K, Casciano C N, Clement R P, Johnson W W. Interaction of common azole antifungals with P glycoprotein.  Antimicrob Agents Chemother. 2002;  46 160-165
    CrossrefPubMedGoogle Scholar
  • 82 Stevens D A, Diaz M, Negroni R et al.. Safety evaluation of chronic fluconazole therapy. Fluconazole Pan-American Study Group.  Chemotherapy. 1997;  43 371-377
    PubMedGoogle Scholar
  • 83 Pappas P G, Kauffman C A, Perfect J et al.. Alopecia associated with fluconazole therapy.  Ann Intern Med. 1995;  123 354-357
    CrossrefPubMedGoogle Scholar
  • 84 Pursley T J, Blomquist I K, Abraham J, Andersen H F, Bartley J A. Fluconazole-induced congenital anomalies in three infants.  Clin Infect Dis. 1996;  22 336-340
    CrossrefPubMedGoogle Scholar
  • 85 Tucker R M, Haq Y, Denning D W, Stevens D A. Adverse events associated with itraconazole in 189 patients on chronic therapy.  J Antimicrob Chemother. 1990;  26 561-566
    CrossrefPubMedGoogle Scholar
  • 86 Sharkey P K, Rinaldi M G, Dunn J F, Hardin T C, Fetchick R J, Graybill J R. High-dose itraconazole in the treatment of severe mycoses.  Antimicrob Agents Chemother. 1991;  35 707-713
    PubMedGoogle Scholar
  • 87 Ahmad S R, Singer S J, Leissa B G. Congestive heart failure associated with itraconazole.  Lancet. 2001;  357 1766-1767
    CrossrefPubMedGoogle Scholar
  • 88 Walsh T J, Pappas P, Winston D J et al.. 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
    CrossrefPubMedGoogle Scholar
  • 89 Ally R, Schurmann D, Kreisel W et al.. 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
    CrossrefPubMedGoogle Scholar
  • 90 Herbrecht R, Denning D W, Patterson T F et al.. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis.  N Engl J Med. 2002;  347 408-415
    CrossrefPubMedGoogle Scholar
  • 91 Scherpbier H J, Hilhorst M I, Kuijpers T W. Liver failure in a child receiving highly active antiretroviral therapy and voriconazole.  Clin Infect Dis. 2003;  37 828-830
    CrossrefPubMedGoogle Scholar
  • 92 Vandecasteele S J, Van Wijngaerden E, Peetermans W E. Two cases of severe phototoxic reactions related to long-term outpatient treatment with voriconazole.  Eur J Clin Microbiol Infect Dis. 2004;  23 656-657
    PubMedGoogle Scholar
  • 93 Curigliano G, Formica V, De Pas T et al.. Life-threatening toxic epidermal necrolysis during voriconazole therapy for invasive aspergillosis after chemotherapy.  Ann Oncol. 2006;  17 1174-1175
    CrossrefPubMedGoogle Scholar
  • 94 McCarthy K L, Playford E G, Looke D F, Whitby M. Severe photosensitivity causing multifocal squamous cell carcinomas secondary to prolonged voriconazole therapy.  Clin Infect Dis. 2007;  44 e55-e56
    CrossrefPubMedGoogle Scholar
  • 95 Tolland J P, McKeown P P, Corbett J R. Voriconazole-induced pseudoporphyria.  Photodermatol Photoimmunol Photomed. 2007;  23 29-31
    CrossrefPubMedGoogle Scholar
  • 96 Philips J A, Marty F M, Stone R M, Koplan B A, Katz J T, Baden L R. Torsades de pointes associated with voriconazole use.  Transpl Infect Dis. 2007;  9 33-36
    CrossrefPubMedGoogle Scholar
  • 97 Tsiodras S, Zafiropoulou R, Kanta E, Demponeras C, Karandreas N, Manesis E K. Painful peripheral neuropathy associated with voriconazole use.  Arch Neurol. 2005;  62 144-146
    CrossrefPubMedGoogle Scholar
  • 98 Skiest D J, Vazquez J A, Anstead G M et al.. Posaconazole for the treatment of azole-refractory oropharyngeal and esophageal candidiasis in subjects with HIV infection.  Clin Infect Dis. 2007;  44 607-614
    CrossrefPubMedGoogle Scholar
  • 99 Cornely O A, Maertens J, Winston D J et al.. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia.  N Engl J Med. 2007;  356 348-359
    CrossrefPubMedGoogle Scholar
  • 100 Vazquez J A, Skiest D J, Nieto L et al.. A multicenter randomized trial evaluating posaconazole versus fluconazole for the treatment of oropharyngeal candidiasis in subjects with HIV/AIDS.  Clin Infect Dis. 2006;  42 1179-1186
    CrossrefPubMedGoogle Scholar
  • 101 Ullmann A J, Lipton J H, Vesole D H et al.. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease.  N Engl J Med. 2007;  356 335-347
    CrossrefPubMedGoogle Scholar
  • 102 Walsh T J, Raad I, Patterson T F et al.. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial.  Clin Infect Dis. 2007;  44 2-12
    CrossrefPubMedGoogle Scholar
  • 103 Raad I I, Graybill J R, Bustamante A B et al.. Safety of long-term oral posaconazole use in the treatment of refractory invasive fungal infections.  Clin Infect Dis. 2006;  42 1726-1734
    CrossrefPubMedGoogle Scholar
  • 104 Rex J H, Bennett J E, Sugar A M et al.. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute.  N Engl J Med. 1994;  331 1325-1330
    CrossrefPubMedGoogle Scholar
  • 105 Rex J H, Pappas P G, Karchmer A W et al.. A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects.  Clin Infect Dis. 2003;  36 1221-1228
    CrossrefPubMedGoogle Scholar
  • 106 Fluckiger U, Marchetti O, Bille J et al.. Treatment options of invasive fungal infections in adults.  Swiss Med Wkly. 2006;  136 447-463
    PubMedGoogle Scholar
  • 107 Slavin M A, Osborne B, Adams R et al.. Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation: a prospective, randomized, double-blind study.  J Infect Dis. 1995;  171 1545-1552
    CrossrefPubMedGoogle Scholar
  • 108 Goodman J L, Winston D J, Greenfield R A et al.. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation.  N Engl J Med. 1992;  326 845-851
    PubMedGoogle Scholar
  • 109 MacMillan M L, Goodman J L, DeFor T E, Weisdorf D J. Fluconazole to prevent yeast infections in bone marrow transplantation patients: a randomized trial of high versus reduced dose, and determination of the value of maintenance therapy.  Am J Med. 2002;  112 369-379
    CrossrefPubMedGoogle Scholar
  • 110 Kaufman D, Boyle R, Hazen K C, Patrie J T, Robinson M, Donowitz L G. Fluconazole prophylaxis against fungal colonization and infection in preterm infants.  N Engl J Med. 2001;  345 1660-1666
    CrossrefPubMedGoogle Scholar
  • 111 Manzoni P, Stolfi I, Pugni L et al.. A multicenter, randomized trial of prophylactic fluconazole in preterm neonates.  N Engl J Med. 2007;  356 2483-2495
    CrossrefPubMedGoogle Scholar
  • 112 Mussini C, Pezzotti P, Miro J M et al.. Discontinuation of maintenance therapy for cryptococcal meningitis in patients with AIDS treated with highly active antiretroviral therapy: an international observational study.  Clin Infect Dis. 2004;  38 565-571
    CrossrefPubMedGoogle Scholar
  • 113 Saag M S, Powderly W G, Cloud G A et al.. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group.  N Engl J Med. 1992;  326 83-89
    PubMedGoogle Scholar
  • 114 Galgiani J N, Catanzaro A, Cloud G A et al.. Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis: a randomized, double-blind trial. Mycoses Study Group.  Ann Intern Med. 2000;  133 676-686
    CrossrefPubMedGoogle Scholar
  • 115 Denning D W, Lee J Y, Hostetler J S et al.. NIAID Mycoses Study Group Multicenter Trial of Oral Itraconazole Therapy for Invasive Aspe rgillosis.  Am J Med. 1994;  97 135-144
    CrossrefPubMedGoogle Scholar
  • 116 Stevens D A, Schwartz H J, Lee J Y et al.. A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis.  N Engl J Med. 2000;  342 756-762
    CrossrefPubMedGoogle Scholar
  • 117 Dismukes W E, Bradsher Jr R W, Cloud G C et al.. Itraconazole therapy for blastomycosis and histoplasmosis. NIAID Mycoses Study Group.  Am J Med. 1992;  93 489-497
    CrossrefPubMedGoogle Scholar
  • 118 Graybill J R, Stevens D A, Galgiani J N, Dismukes W E, Cloud G A. Itraconazole treatment of coccidioidomycosis. NAIAD Mycoses Study Group.  Am J Med. 1990;  89 282-290
    CrossrefPubMedGoogle Scholar
  • 119 Naranjo M S, Trujillo M, Munera M I, Restrepo P, Gomez I, Restrepo A. Treatment of paracoccidioidomycosis with itraconazole.  J Med Vet Mycol. 1990;  28 67-76
    CrossrefPubMedGoogle Scholar
  • 120 Boogaerts M, Winston D J, Bow E J et al.. Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy: a randomized, controlled trial.  Ann Intern Med. 2001;  135 412-422
    PubMedGoogle Scholar
  • 121 Glasmacher A, Prentice A, Gorschluter M et al.. Itraconazole prevents invasive fungal infections in neutropenic patients treated for hematologic malignancies: evidence from a meta-analysis of 3,597 patients.  J Clin Oncol. 2003;  21 4615-4626
    CrossrefPubMedGoogle Scholar
  • 122 Kullberg B J, Sobel J D, Ruhnke M et al.. Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised non-inferiority trial.  Lancet. 2005;  366 1435-1442
    CrossrefPubMedGoogle Scholar
  • 123 Perfect J R, Marr K A, Walsh T J et al.. Voriconazole treatment for less-common, emerging, or refractory fungal infections.  Clin Infect Dis. 2003;  36 1122-1131
    CrossrefPubMedGoogle Scholar
  • 124 Torre-Cisneros JG-RA, Hodges M R, Lutsar I. Voriconazole (VORI) for the treatment of S. apiospermum and S. prolificans infection. Programs and abstracts of the 38th Annual Meeting of the Infectious Diseases Society of America September 7-10, 2000 New Orleans, LA;
    Google Scholar
  • 125 van Burik J A, Hare R S, Solomon H F, Corrado M L, Kontoyiannis D P. Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases.  Clin Infect Dis. 2006;  42 e61-e65
    CrossrefPubMedGoogle Scholar
  • 126 Greenberg R N, Mullane K, van Burik J A et al.. Posaconazole as salvage therapy for zygomycosis.  Antimicrob Agents Chemother. 2006;  50 126-133
    CrossrefPubMedGoogle Scholar
  • 127 Restrepo A, Tobon A, Clark B et al.. Salvage treatment of histoplasmosis with posaconazole.  J Infect. 2007;  54 319-327
    CrossrefPubMedGoogle Scholar
  • 128 Raad I I, Hachem R Y, Herbrecht R et al.. Posaconazole as salvage treatment for invasive fusariosis in patients with underlying hematologic malignancy and other conditions.  Clin Infect Dis. 2006;  42 1398-1403
    CrossrefPubMedGoogle Scholar
  • 129 Anstead G M, Corcoran G, Lewis J, Berg D, Graybill J R. Refractory coccidioidomycosis treated with posaconazole.  Clin Infect Dis. 2005;  40 1770-1776
    CrossrefPubMedGoogle Scholar
  • 130 Segal B H, Barnhart L A, Anderson V L, Walsh T J, Malech H L, Holland S M. Posaconazole as salvage therapy in patients with chronic granulomatous disease and invasive filamentous fungal infection.  Clin Infect Dis. 2005;  40 1684-1688
    CrossrefPubMedGoogle Scholar

John E BennettM.D. 

9000 Rockville Pike, Bldg. 10/11N234

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Email: jbennett@niaid.nih.gov

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