Multicenter prospective observational study of fungal keratitis in Japan: analyses of in vitro susceptibility tests for combinations of drugs.

Keigo Kimura,Chie Sotozono,Seishi Asari,Yuichi Kaji,Toru Tobe,Ryohei Nejima,Shigeki Okamoto,Takashi Miyai,Kazunori Miyata,Takashi Suzuki,Hidetaka Shunji Masaharayokokura,Norio Usui,Kiyofumi Mochizuki,Tamaki Sumi,Etsuko Takamura,Masahiko Fukuda,Hiroto Obata,Yoshitsugu Inoue,Megumi Uematsu,Hiroshi Eguchi,Takeshi Soma,Yu Monden,Toshihiko Uno,Daisuke Todokoro,Manabu Mochizuki,Dai Miyazaki,Eiichi Uchio,Shigeru Kinoshita,Yuichi Ohashi,Noriko Inada,Hiroshi Shiota,Hiroshi Hatano,Tetsuro Oshika,Shigeto Kumakura,Naoyuki Maeda,Kaoru Araki-Sasaki,Tai-Ichiro Chikama,Naoyuki Morishige,Yoshitsugu Tagawa,Kazumi Shinozaki,Koichi Makimura,Hisataka Fujimoto,Takashi Yaguchi,Chika Shigeyasu,Hiroyuki Namba,Shiro Amano,Masafumi Uematsu,Atsuko Sunada,Kei Morohoshi,Koki Matsumoto,Tatsuro Miyamoto,Yoshikazu Shimomura,Masahiko Usui,Saichi Hoshi,Kazuko Kitagawa,Hisashi Nakagawa,Atsushi Shiraishi,Masakazu Yamada,Masashi Sawa ,Hiroshi Gotô ,Naoya Kumagai ,Tohru Kimura ,Kenzo Sonoda ,M Ozawa

doi:10.1007/s10384-022-00907-2

Abstract

To determine the effects of a combination of two antifungal drugs against causative fungi of fungal keratitis in Japan. Multicenter prospective observational study. 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). 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. 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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