The in vitro and in vivo efficacy of fluconazole in combination with farnesol against Candida albicans isolates using a murine vulvovaginitis model

Abstract

Farnesol is a quorum-sensing molecule that inhibits biofilm formation in Candida albicans. Previous in vitro data suggest that, in combination with certain antifungals, farnesol may have an adjuvant anti-biofilm agent. However, the in vivo efficacy of farnesol is very questionable. Therefore, the in vitro and in vivo activity of fluconazole combined with farnesol was evaluated against C. albicans biofilms using fractional inhibitory concentration index (FICI) determination, time-kill experiments and a murine vulvovaginitis model. The median biofilm MICs of fluconazole-sensitive C. albicans isolates ranged between 4 -> 512 mg/L and 150-300 μM for fluconazole and farnesol, respectively. These values were 512 -> 512 mg/L and > 300 μM for fluconazole-resistant clinical isolates. Farnesol decreased the median MICs of fluconazole by 2-64-fold for biofilms. Based on FICI, synergistic interaction was observed only in the case of the sessile SC5314 reference strain (FICIs: 0.16-0.27). In time-kill studies, only the 512 mg/L fluconazole and 512 mg/L fluconazole + 75 μM farnesol reduced biofilm mass significantly at each time point in the case of all isolates. The combination reduced the metabolic activity of biofilms for all isolates in a concentration- and time-dependent manner. Our findings revealed that farnesol alone was not protective in a murine vulvovaginitis model. Farnesol was not beneficial in combination with fluconazole for fluconazole-susceptible isolates, but partially increased fluconazole activity against one fluconazole-resistant isolate, but not the other one.

Optimum Inhibition of Amphotericin-B-Resistant Candida albicans Strain in Single- and Mixed-Species Biofilms by Candida and Non-Candida Terpenoids

“…The MIC values for amphotericin B found in this study were much higher than those reported in various studies for Candida species [29][30][31] which may be attributable to the capacity of C. albicans to develop genetic mutations [32,33], leading to biodiversity [34].…”

In Vivo Applicability of Neosartorya fischeri Antifungal Protein 2 (NFAP2) in Treatment of Vulvovaginal Candidiasis

“…Strains and media. The previously well-characterized FLC-resistant and biofilm-forming C. albicans 27700 strain, isolated from a case of human vulvovaginal candidiasis, was used in the experiments (36). It was maintained on yeast extract-glucose agar slants with KH 2 PO 4 (YEGK) at 4°C.…”

Fungal Quorum-Sensing Molecules: A Review of Their Antifungal Effect against Candida Biofilms

“…A cocktail of Candida -derived regulatory alcohols combined with nanomolar amounts of farnesol was reported to have a similar protective effect by Martins et al (2012) in their murine model of disseminated candidiasis [ 81 ]. Bozó et al (2016) did not find a farnesol-related protective effect against vaginal C. albicans infection [ 82 ], in contrast to the findings of Hisajima et al (2008) [ 80 ]. However, both administered farnesol regimens enhanced the activity of 5 mg/kg daily fluconazole treatment against fluconazole-resistant C. albicans strain [ 82 ].…”

“…Bozó et al (2016) did not find a farnesol-related protective effect against vaginal C. albicans infection [ 82 ], in contrast to the findings of Hisajima et al (2008) [ 80 ]. However, both administered farnesol regimens enhanced the activity of 5 mg/kg daily fluconazole treatment against fluconazole-resistant C. albicans strain [ 82 ]. Similar fluconazole resistance reversion was observed in the case of planktonic cells by Jabra-Rizk et al (2006) [ 76 ] and Cordeiro et al (2013) [ 83 ].…”