title: 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.
authors: Department of Medical Microbiology, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary.
authors: Aliz
authors: A
authors: Bozó
authors: Department of Medical Microbiology, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary.
authors: Marianna
authors: M
authors: Domán
authors: Department of Medical Microbiology, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary.
authors: László
authors: L
authors: Majoros
authors: Department of Medical Microbiology, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary.
authors: Gábor
authors: G
authors: Kardos
authors: Department of Periodontology, Faculty of Dentistry, University of Debrecen, Debrecen, 4032, Hungary.
authors: István
authors: I
authors: Varga
authors: Department of Medical Microbiology, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary. kovacs.renato@med.unideb.hu.
authors: Renátó
authors: R
authors: Kovács
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D002176:Candida albicans / Q000187:drug effects / Q000472:pathogenicity; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology; D004195:Disease Models, Animal; D025141:Drug Resistance, Fungal; D004357:Drug Synergism; D005204:Farnesol / Q000494:pharmacology* / Q000627:therapeutic use*; D005260:Female; D015725:Fluconazole / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D008826:Microbial Sensitivity Tests; D053038:Quorum Sensing / Q000187:drug effects; D014621:Vagina / Q000382:microbiology; D014774:Virulence; D014848:Vulvovaginitis / Q000382:microbiology
chemical_list: D000935:Antifungal Agents; D005204:Farnesol; D015725:Fluconazole
keywords: FIC index; fluconazole-resistant; murine vulvovaginitis; synergy; time-kill experiment