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1 183 Japan Antifungal Surveillance Program (1): ) 1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12) 1) 1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12) fluconazole (FLCZ), itraconazole (ITCZ), voriconazole (VRCZ) flucytosine 4 Candida 556 (97 ) C. albicans 326 (56.6 ) C. glabrata 131 (22.8 ) C. tropicalis 57 (9.9 ) C. parapsilosis 20 (3.5 ) FLCZ C. tropicalis 47 C. albicans 5 trailing growth NCCLS M27-A2 C. tropicalis Candida 0 4 ITCZ VRCZ FLCZ Candida Key words: Candida ( ) 359 ( ) 359 TEL: FAX: kuchida@main.teikyo-u.ac.jp Vol. 14 No

2 184 fluconazole (FLCZ) FLCZ 15 FLCZ in vitro ) FLCZ voriconazole (VRCZ) (2001 ) ) NCCLS M27-A 2) M27-A2 3) 4 FLCZ, itraconazole (ITCZ), flucytosine (5-FC), voriconazole (VRCZ), ITCZ VRCZ 2 2) JSMM 4) NCCLS M27-A2 a) JSMM A-Glutamine NaHCO 3 phenol red RPMI 1640 (Sigma- Aldrich Co.) M morpholinepropanesulfonic acid (Sigma-Aldrich Co.) 10N-NaOH ph O.D. 0.2 IC 80 (MIC) NCCLS M27-A 5) b) NCCLS M27-A2 JSMM Candida Cryptococcus 72 IC 50 (MIC) trailing growth 24 IC 50 (MIC) 2) Aspergillus NCCLS M38-A 6) 7) 8) RPMI 1640 alamar blue (Alamar Bioscience Inc.) IC 80 (MIC) I. C. albicans Table C. albicans C. glabrata 131 C. tropicalis 57 C. parapsi- 56 Vol. 14 No

3 185 Table 1. Species distribution of 576 fungal clinical isolates collected by 11 hospitals in Japan, Japan Antifungal Surveillance Program, 2001 and 2002 Rank Species No. ( ) ofisolates 1 Candida albicans 326 (56.6) 2 Candida glabrata 131 (22.8) 3 Candida tropicalis 57 ( 9.9) 4 Candida parapsilosis 20 ( 3.5) 5 Candida krusei 8( 1.4) 6 Candida lusitaniae 6( 1.1) 6 Trichosporon asahii 6( 1.1) 8 Candida guilliermondii 4( 0.7) 8 Cryptococcus neoformans 4( 0.7) 10 Candida kefyr 2( 0.4) 11 Candida dubliniensis 1( 0.2) 11 Candida inconspicua 1( 0.2) Other yeasts a 6( 1.1) Aspergillus fumigatus 2( 0.4) Other molds b 2( 0.4) a Included are: Rhodotorula mucilaginosa (2), Rhodotorula glutinis (1), Trichosporon pullulans (1), Saccharomyces cerevisiae (1), Cryptococcus humicola (1) b Included are: Penicillium spp. (1), Scedosporium spp. (1) losis 20 Candida C. krusei 8 C. lusitaniae 6 C. guilliermondii 4 C. kefyr 2 C. dubliniensis 1 C. inconspicua 1 Candida /572 Candida 16 Trichosporon asahii 6 Cryptococcus neoformans 4 Rhodotorula mucilaginosa 2 R. glutinis, Cr. humicola, T. pullulans, Saccharomyces cerevisiae 1 Table 2 C. albicans / / /576 C. albicans / / /11 II. Candida Candida JSMM NCCLS M27-A 1 3, 9) MIC FLCZ 64 mg/ml, ITCZ 1 mg/ml, VRCZ 2 mg/ml 5-FC 32 mg/ml Table 3 C. albicans FLCZ 50 MIC 90 MIC 0.5 mg/ml 2 mg/ml 3.7 C. albicans FLCZ 50 MIC 90 MIC FLCZ 1/10 1/ C. albicans 5-FC Non-albicans Candida 8 C. parapsilosis C. guil- Table 2. Specimen-based number of isolates and frequencies of C. albicans isolation Specimens No. of isolates C. albicans Blood, vessel catheter, etc (47.0) Oral cavity, tongue, pharynx, nasal cavity (75.9) Sputum, bronchoalveolar lavage fluid, etc (57.9) Urine (50.9) Bile, stool, gastric juice (57.6) Liquor (spinal fluid, ascites, etc.) 11 4 (38.4) Pus, other exsudates, etc (65.4) Unknown 16 7 (43.8) Total (56.6) Vol. 14 No

4 186 Table 3. In vitro susceptibilities of 556 clinical isolates of Candida species against fluconazole, itraconazole, voriconazole and flucytosine as determined by the Japanese Society for Medical Mycology (JSMM) method Species (no. of isolates) Antifungal agent MIC ( mg/ml) Range 50 a 90 a Resistant b C. albicans (326) Fluconazole Itraconazole Voriconazole Flucytosine C. glabrata (131) Fluconazole Itraconazole Voriconazole Flucytosine C. tropicalis (57) Fluconazole Itraconazole Voriconazole Flucytosine C. parapsilosis (20) Fluconazole Itraconazole Voriconazole Flucytosine C. krusei (8) Fluconazole Itraconazole Voriconazole Flucytosine C. lusitaniae (6) Fluconazole Itraconazole Voriconazole Flucytosine C. guilliermondii (4) Fluconazole Itraconazole Voriconazole Flucytosine C. kefyr (2) fluconazole 0.25, Itraconazole 0.031, Voriconazole , Flucytosine 0.016, 2 0 C. dubliniensis (1) Fluconazole 2 0 Itraconazole Voriconazole Flucytosine C. inconspicua (1) Fluconazole 32 0 Itraconazole Voriconazole 1 0 Flucytosine 16 0 a 50 and 90, MICs at which 50 and 90 of isolated, respectively, are inhibited. b Percent resistant according to the NCCLS interpretative breakpoints criteria. liermondii C. kefyr C. albicans C. parapsilosis FLCZ ITCZ 5.0 non-albicans Candida 4 C. glabrata, C. tropicalis, C. krusei C. lusitaniae FLCZ 58 Vol. 14 No

5 187 Table 4. In vitro susceptibilities of 556 clinical isolates of Candida species against fluconazole, itraconazole, voriconazole and flucytosine as determined by the NCCLS M27-A2 microdilution method Species (no. of isolates) Antifungal agent MIC ( mg/ml) Range 50 a 90 a Resistant b C. albicans (326) Fluconazole Itraconazole Voriconazole Flucytosine C. glabrata (131) Fluconazole Itraconazole Voriconazole Flucytosine C. tropicalis (57) Fluconazole Itraconazole Voriconazole Flucytosine C. parapsilosis (20) Fluconazole Itraconazole Voriconazole Flucytosine C. krusei (8) Fluconazole Itraconazole Voriconazole Flucytosine C. lusitaniae (6) Fluconazole Itraconazole Voriconazole Flucytosine C. guilliermondii (4) Fluconazole Itraconazole Voriconazole Flucytosine C. kefyr (2) fluconazole 0.25, Itraconazole Voriconazole Flucytosine 0.031, 1 0 C. dubliniensis (1) Fluconazole 2 0 Itraconazole Voriconazole Flucytosine C. inconspicua (1) Fluconazole 16 0 Itraconazole Voriconazole Flucytosine 2 0 a 50 and 90, MICs at which 50 and 90 of isolated, respectively, are inhibited. b Percent resistant according to the NCCLS interpretative breakpoints criteria. FLCZ 5.4, 47.4, C. glabrata C. tropicalis ITCZ VRCZ 5-FC C. glabrata C. tropicalis C. tropicalis Vol. 14 No

6 188 NCCLS M27-A2 Table 4 C. albicans Candida 3 50 MIC 90 MIC Table 3 JSMM Ctropicalis 1/2 1/4 FLCZ C. albicans 0.6, C. glabrata 3.8, C. krusei 0 JSMM VRCZ ITCZ C. albicans, C. glabrata C. parapsilosis C. albicans ITCZ VRCZ 0.6, C. glabrata ITCZ VRCZ , C. parapsilosis ITCZ 0 JMSS NCCLS M27-A2 C. tropicalis trailing growth 50 MIC 90 MIC JSMM NCCLS M27-A2 1/ (FLCZ, 47.4 vs 1.8 ; ITCZ, 45.6 vs 3.5 ; VRCZ, 43.9 vs 1.8 ) 5-FC C. tropicalis Candida NCCLS M27-A2 JSMM JSMM C. glabrata 1.8 III. Candida Table 5 Candida Trichosporon asahii 6 Cryptococcus neofor- Table 5. In vitro susceptibilities of 16 isolates of non-candida yeasts against four antifungal agents and four isolates of molds against two antifungal agents Species (no. of isolates) Antifungal agent MIC ( mg/ml) Range Trichosporon asahii (6) Fluconazole 2 8 a /0.5 4 b 8/2 8/4 Itraconazole / / /0.5 Voriconazole / / /0.125 Flucytosine 16 32/ /16 32/ 32 Cryptococcus neoformans (4) Fluconazole 2 8/1 8 4/2 8/8 Itraconazole / / /0.25 Voriconazole / / /0.063 Flucytosine 4/2 4 4/2 4/4 Other yeasts (6) c Fluconazole / /16 64/ 64 Itraconazole / / /1 Voriconazole / / /4 Flucytosine / / / 32 Aspergillus fumigatus (2) Itraconazole 0.5 Voriconazole l Other molds (2) Itraconazole 0.5, 8 Voriconazole 0.25, 0.5 a MICs for yeasts were determined by the JSMM method for yeasts (upper column) and b the NCCLS M27- A2 microdilution method (lower column), and MICs for molds were determined by the JSMM method for molds. c Included are: Rhodotorura mucilaginosa (2), R. glutinis (1), T. pullulans (1), Saccharomyces cerevisiae (1), Cr. humicola (1). d Included are: Penicillium spp. (1), Scedosporium spp. (1). 60 Vol. 14 No

7 189 mans 4 16 Aspergillus fumigatus 2 4 FLCZ, ITCZ, VRCZ 5-FC 4 MIC JSMM NCCLS M27-A2 ITCZ VRCZ 2 MIC JSMM MIC JSMM NCCLS M27-A2 MIC 1/2 1/4 50 MIC 90 MIC MIC T. asahii Cr. neoformans C. albicans 1/10 VRCZ 2 T. asahii 5-FC C. albicans Candida A. fumigatus ITCZ VRCZ amphotericin B (AMPH), 5-FC, miconazole, FLCZ, ITCZ, micafungin, fosfluconazole 7 FLCZ 1989 AIDS FLCZ C. albicans Table 6. Comparison of the results of preceding eight di#erent studies and present study on the in vitro fluconazole-susceptibility of isolates of four major Candida species Surveillance program (reference) Yrs No. of isolates tested Test method a Resistant to fluconazoleb C. albicans C. glabrata C. tropicalis C. parapsilosis CDC (15) h (IC 50 ) c h (IC 50 ) NEMIS (16) h (IC 50 ) EIEIO (17) h (IC 50 ) Sweden (18) h (IC 50 ) Canada (19) h (IC 50 ) h (IC 50 ) SENTRY (20) , h (IC 50 ) JIMS (1) h (IC 50 ) h (IC 50 ) Present study 2001, or 48 h (IC 50 ) d or 48 h (IC 80 ) e a Where otherwise not indicated, the results of NCCLS M-27A test were read after 24 or 48 h using the IC 50 values as the endpoint criteria. b Percent resistant according to the NCCLS interpretive breakpoints criteria for fluconazole (MIC 64 mg/ ml). c Lyon, GM, et al., 40th ICAAC. d Determined by the NCCLS M27-A2 microdilution method. e Determined by the Japanese Society for Medical Mycology (JSMM) method for yeasts. Vol. 14 No

8 190 FLCZ C. krusei C. glabrata 10, 11) 1990 (National Committee for Clinical Laboratory Standards: NCCLS) M27-P 12),M27-T 13) M27-A 2002 M27-A2 NCCLS M27- A2 (NCCLS M27-P, M27-T, M27-A) MIC in vivo trailing growth NCCLS M27-P JSMM JSMM NCCLS M27-T IC 50 IC 80 JSMM trailing growth in vivo 14) NCCLS M27-A2 M27-A Candida FLCZ 5-FC 11 FLCZ, ITCZ, VRCZ 5-FC 4 Candida 97 Candida 4 C. albicans, C. glabrata, C. tropicalis C. parapsilosis Candida FLCZ Table CDC 394 AMPH, 5-FC, FLCZ, ITCZ Kao, et al. 15) National Epidemiology of Mycosis Survey (NEMIS) 16) Emerging Infections and the Epidemiology of Iowa Organisms (EIEIO) Study 17) Candida ) Candida ) SENTRY Antimicrobial Surveillance Program Pfaller, et al. 20) 7 Japan Invasive Mycosis Surveillance (JIMS) Study 1) 7 8 Table 6 Candida 4 C. albicans, C. glabrata, C. tropicalis C. parapsilosis FLCZ (MIC) IC 50 C. albicans C. parapsilosis C. albicans 48 (13 ) C. parapsilosis (15 ) C. glabrata C. tropicalis 6 40, 0 36 C. glabrata 62 Vol. 14 No

9 191 C. krusei FLCZ C. tropicalis FLCZ IC IC IC 50 2 JIMS C. tropicalis trailing growth trailing growth FLCZ C. albicans, C. tropicalis, C. parapsilosis 0 2 FLCZ C. glabrata C. krusei 4 ITCZ VRCZ 5-FC Candida JSMM NCCLS M27- A2 trailing growth Pfizer Pharmaceuticals, New York research grant (Study No.: DIF ) 1) Takakura, S., N. Fujihara, T. Saito, 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: ) National Committee for Clinical Laboratory Standards Reference method for broth dilution antifungal susceptibility testing of yeasts; Approved standard M27-A. National Committee for Clinical Laboratory Standards, Wayne, Pa. 17(9). 3) National Committee for Clinical Laboratory Standards Reference method for broth dilution antifungal susceptibility testing of yeasts; Approved standard M27-A2, Second edition. National Committee for Clinical Laboratory Standards, Wayne, Pa. 22(15). 4) : ) : ) National Committee for Clinical Laboratory Standards Reference method for broth dilution antifungal susceptibility testing of filamentous fungi; Approved standard M38-A. National Committee for Clinical Laboratory Standard, Wayne, Pa. 22(16). 7) Yamaguchi, H., K. Uchida, K. Nagino, et al Usefulness of a colorimetric method for testing antifungal drug susceptibilities of Aspergillus species to voriconazole. J. Infect. Chemother. 8: ) Vol. 14 No

10 : ) Sheehan, D. J., C. A. Hitchcock, C. M. Sibley Current and emerging azole antifungal agents. Clin. Microbiol. Rev. 12: ) Willocks, L., C. L. S. Lee, R. P. Brettle, et al Fluconazole resistance in AIDS patients. J. Antimicrob. Chemother. 23: ) Sanguineti, A., J. K. Carmichael, K. Campbell, Fluconazole-resistant Candida albicans after long-term suppressive therapy. Arch. Intern. Med. 153: ) National Committee for Clinical Laboratory Standards Reference method for broth dilution antifungal susceptibility testing of yeasts; Proposed standard M27-P. National Committee for Clinical Laboratory Standards, Wayne, Pa., 12(25). 13) National Committee for Clinical Laboratory Standards Reference method for broth dilution antifungal susceptibility testing of yeasts; Tentative standard M27-T. National Committee for Clinical Laboratory Standards, Wayne, Pa., 15(10). 14) : ) Kao, A. S., M. E. Brandt, W. R. Pruitt, et al The epidemiology of candidemia in two United States cities: results of a populationbased active surveillance. Clin. Infect. Dis. 29: ) Blumberg,H. M.,W. R.Jarvis,J. M.Soucie,et al Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. Clin. Infect. Dis. 33: ) Diekema, D. J., S. A. Messer, A. B. Brueggemann, et al Epidemiology of candidemia: 3-year results from the emerging infections and epidemiology of Iowa organisms study. J. Clin. Microbiol. 40: ) Chryssanthou, E Trends in antifungal susceptibility among Swedish Candida species bloodstream isolates from 1994 to 1998: Comparison of the E-test and the Sensititre Yeast One Colorimetric Antifungal Panel with the NCCLS M27-A reference method. J. Clin. Microbiol. 39: ) St-Germain, G., M. Laverdiere, R. Pelletier, et al Prevalence and antifungal susceptibility of 442 Candida isolates from blood and other normally sterile sites: results of a 2-year(1996 to 1998) multicenter surveillance study in Quebec, Canada. J.Clin. Microbiol. 39: ) Pfaller, M. A., D. J. Diekema, R. N. Jones, et al Trends in antifungal susceptibility of Candida spp. isolated from pediatric and adult patients with bloodstream infections: SENTRY antimicrobial surveillance program, 1997 to J. Clin. Microbiol. 40: Vol. 14 No

11 193 Nationwide Survey of Antifungal Drug Susceptibility of Clinical Fungal Isolates in Japan from the Japan Antifungal Surveillance Program (JASP), Hideyo Yamaguchi, 1) Katsuhisa Uchida, 1) Katsuko Okuzumi, 2) Toyoko Oguri, 3) Keiko Adachi, 4) Sayoko Kawakami, 5) Masakazu Tosaka, 6) Chieko Kawashima, 7) Yoshiko Hori, 8) 2) Toshimi Kitazawa, 9) Mutsumu Hayashi, 10) Yoshihiko Saito, 11) Kyoko Ozaki, 12) Yayoi Nishiyama 1), Association of Japan Antifungal Susceptibility Surveillance group 1) Teikyo University Institute of Medical Mycology The University of Tokyo Hospital ( Current address: Dokkyo University Hospital) 3) Juntendo University Hospital 4) Tokyo Metropolitan Geriatric Hospital 5) Teikyo University Hospital 6) Kumamoto University Hospital 7) Ashikaga Red Cross Hospital 8) Okayama Saiseikai General Hospital 9) Kitkohkai General Hospital Tane Hospital 10) Jichi Medical School Ohmiya Hospital 11) Tohoku University Hospital 12) Niigata University Hospital We evaluated the antifungal susceptibility profile of 576 recent clinical fungal isolates collected from JASP-participating nationwide hospitals during the two months, June 2001 and March Almost all isolates were Candida species, with fewer numbers of non-candida yeasts (16 isolates) and molds (4 isolates). C. albicans was the most frequent species (56.6 ), followed by C. glabrata (22.8 ), C. tropicalis (9.9 )andc. parapsilosis (3.5 ). The MIC of fluconazole (FLCZ), itraconazole, voriconazole and flucytosine against Candida and other yeast species were determined by the Japanese Society for Medical Mycology (JSMM) microdilution method and the NCCLS M27-A2 microdilution method. Percent resistant by using the interpretive breakpoint criteria of NCCLS to FLCZ was 47 for C. tropicalis and around 5 for other Candida species including C. albicans and C. glabrata when tested by JSMM assay method, while the values were lowered to 0 to 4 for all Candida species when tested by the NCCLS M27-A2 protocol. A similar trend was also seen with the two other azole antifungal drugs. A di#erence in the results obtained between the two assay methods appeared to be due to trailing growth isolates whose azole-susceptibility is usually underestimated in the former method. This study showed that in vitro resistance to these azole antifungal drugs remains uncommon in almost all Candida species. Vol. 14 No

Candida albicans 426 (64.0 ) C. albicans non-albicans

74 2006 1) 2) 1) 3) 4) 5) 6) 1) 2) 3) 4) 5) 6) 17 9 26 18 3 8 2003 10 2004 3 6 9,083 666 (7.3 ) Candida albicans 426 (64.0 ) C. albicans non-albicans 233 (35.0 ) Non-albicans Candida glabrata Candida tropicalis