title: In vitro interactions between farnesol and fluconazole, amphotericin B or micafungin against Candida albicans biofilms.
abstract: OBJECTIVE
  Biofilm formation by Candida albicans poses an important therapeutic challenge in human diseases. Typically, conventional antifungal agents encounter difficulty in treating and fully eradicating biofilm-related infections. Novel therapeutic approaches are needed to treat recalcitrant Candida biofilms. Farnesol is a quorum-sensing molecule, which induces apoptosis, inhibits Ras protein pathways and profoundly affects the morphogenesis of C. albicans. We therefore investigated the interactions between farnesol and different classes of antifungal agents.
  
  
  METHODS
  The combined antifungal effects of triazoles (fluconazole), polyenes (amphotericin B) and echinocandins (micafungin) with farnesol against C. albicans biofilms were assessed in vitro. Antifungal activity was determined by the XTT metabolic assay and confocal microscopy. The nature and the intensity of the interactions were assessed using the Loewe additivity model [fractional inhibitory concentration (FIC) index] and the Bliss independence (BI) model.
  
  
  RESULTS
  Significant synergy was found between each of the three antifungal agents and farnesol, while antagonism was not observed for any of the combinations tested. The greatest synergistic effect was found with the farnesol/micafungin combination, for which the BI-based model showed the observed effects as being 39%-52% higher than expected if the drugs had been acting independently. The FIC indices ranged from 0.49 to 0.79, indicating synergism for farnesol/micafungin and farnesol/fluconazole and no interaction for farnesol/amphotericin B. Structural changes in the biofilm correlated well with the efficacies of these combinations. The maximum combined effect was dependent on the farnesol concentration for micafungin and amphotericin B.
  
  
  CONCLUSIONS
  Farnesol exerts a synergistic or additive interaction with micafungin, fluconazole and amphotericin B against C. albicans biofilms, thus warranting further in vivo study.
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Weill Cornell Medical Center of Cornell University, New York, NY, USA Infectious Disease Unit, 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration Hospital, Thessaloniki, Greece.
authors.forename: Aspasia
authors.initials: A
authors.lastname: Katragkou
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Weill Cornell Medical Center of Cornell University, New York, NY, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: McCarthy
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Alexander
authors.affiliation: Infectious Disease Unit, 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration Hospital, Thessaloniki, Greece.
authors.forename: Charalampos
authors.initials: C
authors.lastname: Antachopoulos
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Joseph
authors.initials: J
authors.lastname: Meletiadis
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, MD, USA Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, MD, USA.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Jabra-Rizk
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Weill Cornell Medical Center of Cornell University, New York, NY, USA.
authors.forename: Vidmantas
authors.initials: V
authors.lastname: Petraitis
authors.affiliation: Infectious Disease Unit, 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration Hospital, Thessaloniki, Greece.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Roilides
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Weill Cornell Medical Center of Cornell University, New York, NY, USA Department of Pediatrics, Weill Cornell Medical College, New York, NY, USA Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA thw2003@med.cornell.edu.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D002176:Candida albicans / Q000187:drug effects* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005204:Farnesol / Q000494:pharmacology*; D015725:Fluconazole / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D018613:Microscopy, Confocal
chemical_list: D000935:Antifungal Agents; D005204:Farnesol; D000666:Amphotericin B; D015725:Fluconazole
keywords: C. albicans; antifungals; combinations