Combination of Miconazole and Domiphen Bromide Is Fungicidal against Biofilms of Resistant <i>Candida</i> spp

Abstract

The occurrence and recurrence of mucosal biofilm-related <i>Candida</i> infections, such as oral and vulvovaginal candidiasis, are serious clinical issues. Vaginal infections caused by <i>Candida</i> spp., for example, affect 70 to 75% of women at least once during their lives. Miconazole (MCZ) is the preferred topical treatment against these fungal infections, yet it has only moderate antibiofilm activity. Through screening of a drug-repurposing library, we identified the quaternary ammonium compound domiphen bromide (DB) as an MCZ potentiator against <i>Candida</i> biofilms. DB displayed synergistic anti-<i>Candida albicans</i> biofilm activity with MCZ, reducing the number of viable biofilm cells 1,000-fold. In addition, the MCZ-DB combination also resulted in significant killing of biofilm cells of azole-resistant <i>C. albicans</i>, <i>C. glabrata</i>, and <i>C. auris</i> isolates. <i>In vivo</i>, the MCZ-DB combination had significantly improved activity in a vulvovaginal candidiasis rat model compared to that of single-compound treatments. Data from an artificial evolution experiment indicated that the development of resistance against the combination did not occur, highlighting the potential of MCZ-DB combination therapy to treat <i>Candida</i> biofilm-related infections.