Journal of Antimicrobial Chemotherapy (2000) 46, 485-487
© 2000 The British Society for Antimicrobial Chemotherapy
Brief reports |
In vitro antifungal activity of FK463, a new water-soluble echinocandin-like lipopeptide
Department of Obstetrics and Gynaecology, School of Medicine, Gifu University, 40 Tsukasa-machi, Gifu City, Gifu 500-8705, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and methodsResults and discussionReferences |
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The antifungal activity of FK463 against 72 recent clinical isolates of Candida albicans (24), Candida glabrata (17), Candida tropicalis (11), Candida krusei (8) and Candida parapsilosis (12) was compared with those of amphotericin B, fluconazole and itraconazole by means of a broth microdilution method specified by the National Committee for Clinical Laboratory Standards (NCCLS) document M27-A. The lowest drug concentration at which 90% of the population was inhibited (MIC90) of FK463 against C. albicans, C. glabrata, C. tropicalis, C. krusei and C. parapsilosis was 0.0156, 0.0156, 0.0313, 0.125 and 1 mg/L, respectively. FK463 exhibited broad-spectrum activity against clinically important Candida spp. (MIC range
0.0039–2 mg/L), and its MICs for such fungi were lower than those of other antifungal agents tested. The minimum fungicidal concentrations for Candida spp. did not differ by more than two-fold from the MICs. Results from pre-clinical evaluations performed to date indicate that FK463 should be a potent parenteral antifungal agent. |
Introduction |
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TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
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After the 1980s, the increase in immunocompromised hosts as a result of the spread of human immunodeficiency virus infection, the increased use of immunosuppressive agents in organ transplantations, aggressive anti-cancer chemotherapy and improved life-saving medical techniques necessitating indwelling catheters has led to a substantial increase in the occurrence of serious fungal infections.1
Progress in the development of both topical and systemic antifungal agents lagged behind that of antibacterial agents, due in part to the intensive research efforts in the area of antibacterial therapy that began in the 1940s following the large-scale production of penicillin and also to the relatively low incidence of serious fungal infections compared with that of bacterial infections.2
Recently, new classes of antifungal agents such as the candins, the nikkomycins and the pradimicins–benanomicins have been studied.3
FK463 is a new parenterally administered antifungal drug undergoing phase II clinical trials. It is a semisynthetic derivative of FR901379, a water-soluble cyclic hexapeptide with a fatty acyl side chain similar in structure to the echinocandin class of antifungal agents. The addition of the fatty acid side chain to FR901379 has improved its antifungal potency. FK463 has been shown to have potent fungistatic and fungicidal activity against Candida spp.4 Pharmacokinetic studies in clinical trials suggest that AUC0–
and Cmax increase in a dose proportional manner and a mean value of t1/2 was estimated as 14.7 h.5
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
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Compounds
FK463 was synthesized by Fujisawa Pharmaceutical Co., Ltd. (Osaka, Japan). Amphotericin B, fluconazole and itraconazole were purchased from Bristol-Myers Squibb (Tokyo, Japan), Pfizer (Groton, CT, USA) and Janssen– Kyowa (Tokyo, Japan), respectively.
Organisms
Seventy-two recent clinical isolates of Candida albicans (24), Candida glabrata (17), Candida tropicalis (11), Candida krusei (8) and Candida parapsilosis (12) were used.
MIC assays
Antifungal susceptibility assays to determine the MICs of FK463 and other reference antifungal agents were performed by the broth microdilution method according to M27-A guidelines recommended by the National Committee for Clinical Laboratory Standards (NCCLS).6 The MICs of FK463 and amphotericin B for Candida spp. were defined as the lowest concentrations at which no visible growth was observed, and for fluconazole and itraconazole, the MICs were defined as the lowest concentrations at which a prominent decrease in turbidity was observed.
Minimal fungicidal concentration (MFC) assays
MFCs were determined by the microdilution reference method with an inoculum size of 1.0–2.5 x 104 cells/mL of Candida spp.5 After MIC measurement, the microtitre plates were shaken and a 1 µL aliquot was removed from each well of the microtitre plate and transferred to a single-reservoir plate containing Sabouraud dextrose agar. These were incubated for 24–72 h at 35°C. The MFC was defined as the minimum concentration at which no visible growth was observed. This represents killing of >90% of the original inoculum.
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Results and discussion |
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TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
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The MICs and MFCs of FK463 are shown in the Table
. The MIC50s of FK463 for C. albicans, C. glabrata, C. tropicalis, C. krusei and C. parapsilosis were 0.0078, 0.0156, 0.0313, 0.125 and 1 mg/L, respectively. The MIC90s of FK463 for C. albicans, C. glabrata, C. tropicalis, C. krusei and C. parapsilosis were 0.0156, 0.0156, 0.0313, 0.125 and 1 mg/L, respectively.
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The management of serious infections due to Candida spp., which are becoming increasingly prevalent, is problematic because of the increasing incidence of non-albicans species and the emergence of non-albicans isolates resistant to both amphotericin B and the newer azoles.7
FK463 exhibited broad-spectrum activity against clinically important Candida spp. (MIC range 0.0039–2 mg/L), and its MICs for such fungi were lower than those of other antifungal agents tested. The MFCs for Candida spp. did not differ more than two-fold from the MICs. Results from pre-clinical evaluations performed to date indicate that FK463 should be a potent parenteral antifungal agent.
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Notes |
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* Corresponding author. Tel: +81-58-267-2631; Fax: +81-58-265-9006; E-mail: mikamo{at}cc.gifu-u.ac.jp
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References |
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TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
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1 . Ghannoum, M. A. (1997). Future of antimycotic therapy. Dermatologic Therapy 3, 104–11.
2 . Ghannoum, M. A., Rex, J. H. & Galgiani, J. N. (1996). Susceptibility testing of fungi: current status of correlation of in vitro data with clinical outcome. Journal of Clinical Microbiology 34, 489–95.[Abstract]
3 . Kauffman, C. & Carver, P. L. (1997). Antifungal agents in the 1990s. Current status and future developments. Drugs 53, 539–49.[Web of Science][Medline]
4 . Matsunoto, S., Wakai, Y., Maki, K., Watabe, E., Ushitani, T., Otomo, K. et al. (1998). Efficacy of FK463, a novel water-soluble echinocandin-like lipopeptide, in murine models of disseminated candidiasis. In Program and Abstracts of the Thirty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA. Abstract F142, p. 268. American Society for Microbiology, Washington, DC.
5 . Azuma, J., Yamamoto, I., Ogura, M., Mukai, T., Suematsu, H., Kageyama, H. et al. (1998). Phase I study of FK463, a new antifungal agent, in healthy adult male volunteers. In Program and Abstracts of the Thirty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA. Abstract F146, p. 269. American Society for Microbiology, Washington, DC.
6 . National Committee for Clinical Laboratory Standards. (1997). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts: Approved Standard Document M27-A. NCCLS, Villanova, PA.
7 . Nguyen, M. H., Peacock, J. E. J., Morris, A. J., Tanner, D. C., Nguyen, M. L., Snydman, D. R. et al. (1996). The changing face of candidemia: emergence of non-Candida albicans species and antifungal resistance. American Journal of Medicine 100, 617–23.[Web of Science][Medline]
Received 4 February 2000; returned 25 April 2000; revised 12 May 2000; accepted 22 May 2000
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