title: In vivo activity of terpinen-4-ol, the main bioactive component of Melaleuca alternifolia Cheel (tea tree) oil against azole-susceptible and -resistant human pathogenic Candida species.
abstract: BACKGROUND
  Recent investigations on the antifungal properties of essential oil of Melaleuca alternifolia Cheel (Tea Tree Oil, TTO) have been performed with reference to the treatment of vaginal candidiasis. However, there is a lack of in vivo data supporting in vitro results, especially regarding the antifungal properties of TTO constituents. Thus, the aim of our study was to investigate the in vitro and the in vivo anti-Candida activity of two critical bioactive constituents of TTO, terpinen-4-ol and 1,8-cineole.
  
  
  METHODS
  Oophorectomized, pseudoestrus rats under estrogen treatment were used for experimental vaginal infection with azole (fluconazole, itraconazole) -susceptible or -resistant strains of C. albicans. All these strains were preliminarily tested for in vitro susceptibility to TTO, terpinen-4-ol and 1,8-cineole for their antifungal properties, using a modification of the CLSI (formerly NCCLS) reference M27-A2 broth micro-dilution method.
  
  
  RESULTS
  In vitro minimal inhibitory concentrations (MIC90) values were 0.06% (volume/volume) for terpinen-4-ol and 4% (volume/volume) for 1,8-cineole, regardless of susceptibility or resistance of the strains to fluconazole and itraconazole. Fungicidal concentrations of terpinen-4-ol were equivalent to the candidastatic activity. In the rat vaginal infection model, terpinen-4-ol was as active as TTO in accelerating clearance from the vagina of all Candida strains examined.
  
  
  CONCLUSIONS
  Our data suggest that terpinen-4-ol is a likely mediator of the in vitro and in vivo activity of TTO. This is the first in vivo demonstration that terpinen-4-ol could control C. albicans vaginal infections. The purified compound holds promise for the treatment of vaginal candidiasis, and particularly the azole-resistant forms.
authors.affiliation: Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. mondello@iss.it
authors.forename: Francesca
authors.initials: F
authors.lastname: Mondello
authors.forename: Flavia
authors.initials: F
authors.lastname: De Bernardis
authors.forename: Antonietta
authors.initials: A
authors.lastname: Girolamo
authors.forename: Antonio
authors.initials: A
authors.lastname: Cassone
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Salvatore
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001393:Azoles / Q000494:pharmacology; D002175:Candida / Q000145:classification / Q000187:drug effects*; D002176:Candida albicans / Q000187:drug effects; D002181:Candidiasis, Vulvovaginal / Q000188:drug therapy* / Q000382:microbiology; D025141:Drug Resistance, Fungal; D005260:Female; D015725:Fluconazole / Q000494:pharmacology; D006801:Humans; D031650:Melaleuca / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D051381:Rats; D020947:Tea Tree Oil / Q000737:chemistry / Q000494:pharmacology*; D013729:Terpenes / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D013729:Terpenes; C034019:terpinenol-4; D020947:Tea Tree Oil; D015725:Fluconazole