Novel and potent antimicrobial effects of caspofungin on drug-resistant Candida and bacteria.

Sumiyoshi, Makoto; Miyazaki, Taiga; Makau, Juliann Nzembi; Mizuta, Satoshi; Tanaka, Yoshimasa; Ishikawa, Takeshi; Makimura, Koichi; Hirayama, Tatsuro; Takazono, Takahiro; Saijo, Tomomi; Yamaguchi, Hiroyuki; Shimamura, Shintaro; Yamamoto, Kazuko; Imamura, Yoshifumi; Sakamoto, Noriho; Obase, Yasushi; Izumikawa, Koichi; Yanagihara, Katsunori; Kohno, Shigeru; Mukae, Hiroshi

Echinocandins, including caspofungin, micafungin, and anidulafungin, are first-line antifungal agents for the treatment of invasive candidiasis. They exhibit fungicidal activity by inhibiting the synthesis of β-1,3-D-glucan, an essential component of the fungal cell wall. However, they are active only against proliferating fungal cells and unable to completely eradicate fungal cells even after a 24 h drug exposure in standard time-kill assays. Surprisingly, we found that caspofungin, when dissolved in low ionic solutions, had rapid and potent antimicrobial activities against multidrug-resistant (MDR) Candida and bacteria cells even in non-growth conditions. This effect was not observed in 0.9% NaCl or other ion-containing solutions and was not exerted by other echinocandins. Furthermore, caspofungin dissolved in low ionic solutions drastically reduced mature biofilm cells of MDR Candida auris in only 5 min, as well as Candida-bacterial polymicrobial biofilms in a catheter-lock therapy model. Caspofungin displayed ion concentration-dependent conformational changes and intracellular accumulation with increased reactive oxygen species production, indicating a novel mechanism of action in low ionic conditions. Importantly, caspofungin dissolved in 5% glucose water did not exhibit increased toxicity to human cells. This study facilitates the development of new therapeutic strategies in the management of catheter-related biofilm infections.