Keigo Kimura1, Yoshitsugu Inoue2, Seishi Asari1, Atsuko Sunada1, Yuichi Ohashi3, Yoshikazu Shimomura4, Chie Sotozono5, Hiroshi Hatano6, Masahiko Fukuda7, Hiroshi Eguchi8, Kaoru Araki-Sasaki9, Takashi Suzuki10, Saichi Hoshi11, Toru Tobe12, Takashi Yaguchi13, Koichi Makimura14. 1. Laboratory for Clinical Investigation, Osaka University Hospital, Osaka, Japan. 2. Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago, Tottori, 683-8504, Japan. yoinoue@grape.med.tottori-u.ac.jp. 3. Department of Ophthalmology, Minami-Matsuyama Hospital, Matsuyama, Ehime, Japan. 4. Department of Ophthalmology, Fuchu Hospital, Izumi, Osaka, Japan. 5. Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan. 6. Hatano Eye Clinic, Fujisawa, Kanagawa, Japan. 7. Department of Ophthalmology, Kindai University Nara Hospital, Ikoma, Nara, Japan. 8. Department of Ophthalmology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan. 9. Department of Ophthalmology, Kansai Medical University, Hirakata, Osaka, Japan. 10. Department of Ophthalmology, Faculty of Medicine, Toho University, Tokyo, Japan. 11. Horikiri Eye Clinic, Tokyo, Japan. 12. Department of Biomedical Informatics, Osaka University Graduate School of Medicine, Osaka, Japan. 13. Medical Mycology Research Center, Chiba University, Chiba, Japan. 14. Institute of Medical Mycology, Teikyo University, Tokyo, Japan.
Abstract
PURPOSE: To determine the effects of a combination of two antifungal drugs against causative fungi of fungal keratitis in Japan. STUDY DESIGN: Multicenter prospective observational study. METHODS: Eighteen isolates of yeast-like fungi and 22 isolates of filamentous fungi collected by the Multicenter Prospective Observational Study of Fungal Keratitis in Japan were studied. Specially manufactured minimum inhibitory concentration (MIC) measurement plates were used to test the effectiveness of 10 combinations of two antifungal drugs against the isolates. The combinations were pimaricin (PMR) + voriconazole (VRCZ), PMR + fluconazole (FLCZ), PMR + miconazole (MCZ), PMR + micafungin (MCFG), VRCZ + FLCZ, VRCZ + MCZ, VRCZ + MCFG, VRCZ + amphotericin-B (AMPH-B), MCZ + FLCZ, and MCZ + MCFG. The checkerboard microdilution method was used, and the fractional inhibitory concentration (FIC) index was calculated based on the guidelines of The Clinical & Laboratory Standards Institute (CLSI). RESULTS: In yeast-like fungi, additive effects were observed between PMR and MCFG in 77.8% of the isolates, and they were also observed between the azoles. Synergistic effects were observed on 11.1% of the isolates for MCZ and FLCZ. On the other hand, antagonistic effects were present between PMR and azoles with 88.9% between PMR and VRCZ, 72.2% between PMR and FLCZ, and 94.4% between PMR and MCZ. In filamentous fungi, additive effects were observed between PMR and MCFG in 40.9% of the isolates, and between VRCZ and MCZ in 40.9% of the isolates. Antagonistic effects were observed for PMR and the azoles. CONCLUSIONS: The combination of drugs prescribed for fungal keratitis incurs a possibility of synergistic, additive, indifferent, or antagonistic effects, depending on drug combinations and fungal strains.
PURPOSE: To determine the effects of a combination of two antifungal drugs against causative fungi of fungal keratitis in Japan. STUDY DESIGN: Multicenter prospective observational study. METHODS: Eighteen isolates of yeast-like fungi and 22 isolates of filamentous fungi collected by the Multicenter Prospective Observational Study of Fungal Keratitis in Japan were studied. Specially manufactured minimum inhibitory concentration (MIC) measurement plates were used to test the effectiveness of 10 combinations of two antifungal drugs against the isolates. The combinations were pimaricin (PMR) + voriconazole (VRCZ), PMR + fluconazole (FLCZ), PMR + miconazole (MCZ), PMR + micafungin (MCFG), VRCZ + FLCZ, VRCZ + MCZ, VRCZ + MCFG, VRCZ + amphotericin-B (AMPH-B), MCZ + FLCZ, and MCZ + MCFG. The checkerboard microdilution method was used, and the fractional inhibitory concentration (FIC) index was calculated based on the guidelines of The Clinical & Laboratory Standards Institute (CLSI). RESULTS: In yeast-like fungi, additive effects were observed between PMR and MCFG in 77.8% of the isolates, and they were also observed between the azoles. Synergistic effects were observed on 11.1% of the isolates for MCZ and FLCZ. On the other hand, antagonistic effects were present between PMR and azoles with 88.9% between PMR and VRCZ, 72.2% between PMR and FLCZ, and 94.4% between PMR and MCZ. In filamentous fungi, additive effects were observed between PMR and MCFG in 40.9% of the isolates, and between VRCZ and MCZ in 40.9% of the isolates. Antagonistic effects were observed for PMR and the azoles. CONCLUSIONS: The combination of drugs prescribed for fungal keratitis incurs a possibility of synergistic, additive, indifferent, or antagonistic effects, depending on drug combinations and fungal strains.
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