Voriconazole. Voriconazole VRCZ ITCZ

Transcription

1 fluconazole itraconazole in vitro in vivo Candida spp. C. glabrata C. krusei Cryptococcus neoformans in vitro Aspergillus spp. in vitro in vivo Aspergillus fumigatus Candida albicans C. krusei Key words: voriconazole new-generation azole antifungal agent in vitro antifungal activity selective action mechanism in vivo antifungal activity fluconazole itraconazole amphotericin B voriconazole 359 in vitro in vivo I 4α P4504DM Fig. Candida albicans Aspergillus fumigatus 3 Table IC50 C. albicans A. fumigatus 3 9

2 4 HO CH3 Lanosterol P4504DM HO HO Ergosterol Target Molecule: Lanosterol 4 -demethylase P4504DM HO Fig.. Target site of voriconazole action on the ergosterol biosynthesis pathway in fungi. Table. Activity of voriconazole, fluconazole, ketoconazole, and itraconazole on sterol biosynthesis in fungal and mammalian enzymatic systems Antifungal agent Ketoconazole Fluconazole Median inhibitory concentration IC50 for ergosterol/cholesterol biosynthetic systems from: mol/l Rat liver Candida albicans b) Aspergillus fumigatus Measured based on the radioactivity of 4 C mevalonic acid incorporated into cholesterol rat liver or ergosterol fungi with or without testing antifungal agents. Numbers in, brackets are IC50 for C. albicans or A. fumigatus to that for the rat liver. Note: Data is from Hitchcock et al 3. ketoconazole KCZ II In vitro in vitro Espinel-Ingroff 5 Johnson 6 7,8 in vitro Aspergillus spp. Tables 3 Candida spp. MIC90 C. krusei MIC C. albicans µ g ml C. glabrata µ g ml C. parapsilosis µ g ml C. tropicalis µ g ml C. krusei µ g ml Candida C. glabrata C. krusei Cryptococcus neoformans Trichosporon asahii MIC90 µ g ml MIC µ g ml Aspergillus A. fumigatus A. flavus A. terreus A. niger MIC µ g ml Scedosporium apiospermum MIC µ g ml

3 Table. In vitro antifungal activity of voriconazole against pathogenic yeasts Organism Number of isolates Antifungal agent Range MIC g/ml 50% 90% Candida albicans Candida glabrat Candida guilliermondii c - - Candida krusei Candida parapsilosis Candida tropicalis Cryptococcus neoformans Trichosporon asahii , voriconazole;, itraconazole;, fluconazole;, amphotericin B. Determined by broth microdilution with RPMI640 medium proposed by the Japanese Society for Medical Mycology 7. c Not determined. Candida spp. Aspergillus spp. in vitro MIC MIC50 MIC90 Table 4 Aspergillus spp. Hitchcock 3 Aspergillus spp. MFC MIC S. apiospermum Fusarium spp. Aspergillus spp. 9,0 Aspergillus Table P4504DM III In vivo in vivo,

4 Table 3. In vitro antifungal activity of voriconazole for Aspergillus spp. Organism Number of isolates Antifungal agent Range MIC g/ml 50% 90% Aspergillus fumigatus Aspergillus flavus Aspergillus niger Aspergillus terreus 5 - -, voriconazole;, itraconazole;, fluconazole;, amphotericin B. Determined by broth microdilution with RPMI640 medium proposed by the Japanese Society for Medical Mycology 7. Table 4. Comparison of voriconazole MIC and MFC for Aspergillus spp. Strain MIC g/ml MFC g/ml MFC/MIC A. fumigatus HO A. fumigatus HO6. A. flavus HO5.0 A. niger HO Determined by broth microdilution with high-resolution medium. Determined by broth microdilution 90% kill with high-resolution medium. Note: Data is from Hitchcock et al 3. C. krusei 3,6 4 7,8 6 A. fumigatus 7 A. fumigatus HO mg kg 4 Table 5 5 mg kg 00 5 mg kg 50 0 mg kg 00 A. fumigatus 7 A. fumigatus HO mg kg 4 6 mg kg

5 Table 5. Efficacy of voriconazole in the guinea pig model of systemic aspergillosis due to Aspergillus fumigatus Vehicle Treatment Dose mg/kg Survival % 4.0 /5 Eradication % 0 0/5 Liver fungal burden Mean log0 CFU/g SD /8 0 0/ bid 4 days /0 0 0/ / / / / /5 0 0/ bid 4 days /8 7. / / / P 0.00 versus values obtained with the vehicle control group, calculated by Student s independent t-test. P 0.0 versus values obtained with the vehicle control group, calculated by Student s independent t-test. Note: Data is from Hitchcock et al 7. Table 6. Efficacy of voriconazole in the guinea pig model of invasive pulmonary aspergillosis due to Aspergillus fumigatus Vehicle Treatment bid 6 7 days Dose mg/kg 4 8 Survival rate % 84. 6/ / / / / Eradication rate % 5.3 /9 5.4 /3 4.3 / / / Lung fungal burden Mean log0 CFU/g SD /8. / bid 6 7 days /8. / /6 6.7 / P 0.00 versus values obtained with the vehicle control group, calculated by Student s independent t-test. P 0.0 versus values obtained with the comparable dose itraconazole group, calculated by Student s independent t-test. Note: Data is from Hitchcock et al 7. Table 6 4 8mg kg 3 C. albicans 8 MIC 00 µ g ml C. albicans YO Table mg kg 0 mg kg 0 mg kg 4 C. krusei 8 C. krusei YO Table mg kg 0 mg kg 5 0 mg kg 0 mg kg C. krusei in vivo IV in vitro

6 Table 7. Efficacy of voriconazole in the guinea pig model of systemic candidiasis due to fluconazole-resistant Candida albicans Vehicle Treatment Dose mg/kg Survival % /5 Kidney fungal burden Mean log0 CFU/g SD / bid 4 days / / / bid 4 days / / Fluconazole bid 4 days / P 0.00 versus values obtained with the vehicle control group, itraconazole 0 mg/kg group and fluconazole 0 mg/kg group, calculated by Student s independent t-test. Note: Data is from Troke et al 8. Table 8. Efficacy of voriconazole in the guinea pig model of systemic candidiasis due to fluconazole-resistant Candida krusei Vehicle Treatment bid 7 days Dose mg/kg 5 0 Survival % 0 0/ /8 Kidney fungal burden Mean log0 CFU/g SD bid 7 days Fluconazole bid 7 days 0.5 / P 0.00 versus values obtained with the vehicle control group, comparable dose itraconazole group and fluconazole group, calculated by Student s independent t-test. Note: Data is from Troke et al 8. Aspergillus spp. Aspergillus C. albicans C. krusei in vitro in vitro in vivo 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 3: 73 74, 003 Sanati H, Belanger P, Fratti B, et al: A new triazole,

7 voriconazole UK-09, 496, blocks sterol biosynthesis in Candida albicans and Candida krusei. Antimicrob Agents Chemother 4: , Hitchcock C A, Pye G W, Oliver G P, et al: UK-09, 496, a novel, wide-spectrum triazole derivative for the treatment of fungal infection: antifungal activity and selectivity in vitro. In Program and Abstracts of the 35 th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 995, Abstract F76, p. 5, American Society for Microbiology, Washington, DC, Ch vez M, Bernal S, Valverde A, et al: In-vitro activity of voriconazole UK-09, 496, LY and other antifungal agents against oral Candida spp. isolates from HIV-infected patients. J Antimicrob Chemother 44: , Maesaki S, Iwakawa J, Higashiyama Y, et al: Antifungal activity of a new triazole, voriconazole UK-09, 496, against clinical isolates of Aspergillus spp. J Infect Chemother 6: 0 03, Pfaller M A, Diekema D J, Jones R N, et al: International surveillance of blood stream infections due to Candida species: frequency of occurrence and in vitro susceptibilities to fluconazole, ravuconazole, and voriconazole of isolates collected from 997 through 999 in the SENTRY antimicrobial surveillance program. J Clin Microbiol 39: , 00 7 Pfaller M A, Diekema D J, Jones R N, et al: Trends in antifungal susceptibility of Candida spp. isolated from pediatric and adult patients with blood stream infections: SENTRY Antimicrobial Surveillance Program, 997 to 000. J Clin Microbiol 40: , 00 8 Pelletier R, Loranger L, Marcotte H, et al: and fluconazole susceptibility of Candida isolates. J Med Microbiol 5: , 00 9 Pfaller M A, Messer S A, Hollis R J, et al: 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 46: 73 77, 00 0 Serrano M C, Morilla D, Valverde A, et al: Comparison of Etest with modified broth microdilution method for testing susceptibility of Aspergillus spp. to voriconazole. J Clin Microbiol 4: , 003 Takakura S, Fujihara N, Saito T, et al: National surveillance of species distribution in blood isolates of Candida species in Japan and their susceptibility to six antifungal agents including voriconazole and micafungin. J Antimicrob Chemother 53: 83 89, 004 Pfaller M A, Diekema D J, Messer S A, et al: Activities of fluconazole and voriconazole against,586 recent clinical isolates of Candida species determined by broth microdilution, disk diffusion, and Etest methods: report from the ARTEMIS Global Antimicrobial Susceptibility Program, 00. J Clin Microbiol 4: , Pfaller M A, Messer S A, Boyken L, et al: In vitro activities of voriconazole, posaconazole, and fluconazole against 4,69 clinical isolates of Candida spp. and Cryptococcus neoformans collected during 00 and 00 in the ARTEMIS Global Antifungal Surveillance Program. Diag Microbiol Infect Dis 48: 04 05, van Duin D, Cleare W, Zaragoza O, et al: Effects of voriconazole on Cryptococcus neoformans. Antimicrob Agents Chemother 48: 04 00, Espinel-Ingroff A, Boyle K, Sheehan D J: In vitro antifungal activities of voriconazole and reference agents as determined by NCCLS methods: review of the literature. Mycopathologia 50: 0 5, 00 6 Johnson L B, Kauffman C A: : a new triazole antifungal agent. Clin Infect Dis 36: , : 6 86, : 39 57, Manavathu E K, Cutright J L, Chandrasekar P H: Organism-dependent fungicidal activity of azoles. Antimicrob Agents Chemother 4: , Espinel-Ingroff A: In vitro fungicidal activities of voriconazole, itraconazole, and amphotericin B against opportunistic moniliaceous and dematiaceous fungi. J Clin Microbiol 39: , 00 Murphy M, Bernard E M, Ishimaru T, et al: Activity of voriconazole UK-09, 496 against clinical isolates of Aspergillus species and its effectiveness in an experimental model of invasive aspergillosis. Antimicrob Agents Chemother 4: , 997 George D, Miniter P, Andrioli V T: Efficacy of UK-09, 496, a new azole antifungal agent, in an experimental model of invasive aspergillosis. Antimicrob Agents Chemother 40: 86 9, Martin M V, Yates J, Hitchcock C A: Comparison of voriconazole UK-09, 496 and itraconazole in prevention and treatment of Aspergillus fumigatus endocarditis in guinea pigs. Antimicrob Agents Chemother 4: 3 6, Chandrasekar P H, Cutright J, Manavathu E: Efficacy of voriconazole against invasive pulmonary aspergillosis in a guinea-pig model. J Antimicrob Chemother 45: , Kirkpatrick W R, McAtee R K, Fothergill A W, et al: Efficacy of voriconazole in a guinea pig model of disseminated invasive aspergillosis. Antimicrob Agents Chemother 44: , Ghannoum M A, Okogbule-Wonodi I, Bhat N, et al: Antifungal activity of voriconazole UK-09, 496, fluconazole and amphotericin B against hematogenous Candida krusei infection in neutropenic guinea pig model. J Chemother : 34 39, Hitchcock C A, Andrews R J, Lewis B G H, et al: UK- 09, 496, a novel, wide-spectrum triazole derivative for the treatment of fungal infections: antifungal activity in experimental infections with Aspergillus. In Program and Abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy,

8 San Francisco, 995, Abstract F7, p.5, American Society for Microbiology, Washington, DC, Troke P F, Brammer K W, Hitchcock C A, et al: UK- 09, 496, a novel, wide-spectrum triazole derivative for the treatment of fungal infections: activity in systemic candidiasis models and early clinical efficacy in oropharyngeal candidiasis OPC. In Program and Abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 995, Abstract F73, p.5, American Society for Microbiology, Washington, DC, 995 Antifungal activity of voriconazole Hideyo Yamaguchi Teikyo University Institute of Medical Mycology, 359 Otsuka, Hachioji, Tokyo, Japan, a new-generation azole antifungal agent with a wide antifungal spectrum, like all azole agents, selectively inhibits fungal ergosterol biosynthesis. We review experimental data obtained by Pfizer s research group and ours on the in vitro and in vivo antifungal activity of compared to itraconazole and fluconazole, along with data published elsewhere. has substantial in vitro activity against Candida spp., including -insusceptible C. glabrata and C. krusei, Cryptococcus neoformans and other yeasts that is similar to and superior to. had potent and fungicidal in vitro activity against most Aspergillus spp. and several other mycelial fungi. In vivo activity was evaluated in guinea pig models of systemic and invasive pulmonary aspergillosis and of systemic candidiasis due to a resistant C. albicans and C. krusei, using and as reference drugs. In all of these animal models, was more effective than similar or higher doses of reference drugs in the survival of infected animals, clearance of challenged pathogenic fungi, and or reduction of fungal burden in infected tissues. thus appears to be an attractive option in the treatment of invasive and disseminated fungal infections.