title: In vitro drug interaction modeling of combinations of azoles with terbinafine against clinical Scedosporium prolificans isolates.
abstract: The in vitro interaction between terbinafine and the azoles voriconazole, miconazole, and itraconazole against five clinical Scedosporium prolificans isolates after 48 and 72 h of incubation was tested by a microdilution checkerboard (eight-by-twelve) technique. The antifungal effects of the drugs alone and in combination on the fungal biomass as well as on the metabolic activity of fungi were measured using a spectrophotometric method and two colorimetric methods, based on the lowest drug concentrations showed 75 and 50% growth inhibition (MIC-1 and MIC-2, respectively). The nature and the intensity of the interactions were assessed using a nonparametric approach (fractional inhibitory concentration [FIC] index model) and a fully parametric response surface approach (Greco model) of the Loewe additivity (LA) no-interaction theory as well as a nonparametric (Prichard model) and a semiparametric response surface approaches of the Bliss independence (BI) no-interaction theory. Statistically significant synergy was found between each of the three azoles and terbinafine in all cases, although with different intensities. A 27- to 64-fold and 16- to 90-fold reduction of the geometric mean of the azole and terbinafine MICs, respectively, was observed when they were combined, resulting in FIC indices of <1 to 0.02. Using the MIC-1 higher levels of synergy were obtained, which were more consistent between the two incubation periods than using the MIC-2. The strongest synergy among the azoles was found with miconazole using the BI-based models and with voriconazole using the LA-based models. The synergistic effects both on fungal growth and metabolic activity were more potent after 72 h of incubation. Fully parametric approaches in combination with the modified colorimetric method might prove useful for testing the in vitro interaction of antifungal drugs against filamentous fungi.
authors.affiliation: Department of Medical Microbiology, University Medical Center Nijmegen, Nijmegen, The Netherlands.
authors.forename: Joseph
authors.initials: J
authors.lastname: Meletiadis
authors.forename: Johan W
authors.initials: JW
authors.lastname: Mouton
authors.forename: Jacques F G M
authors.initials: JF
authors.lastname: Meis
authors.forename: Paul E
authors.initials: PE
authors.lastname: Verweij
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D004347:Drug Interactions; D008826:Microbial Sensitivity Tests; D009281:Naphthalenes / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D021681:Scedosporium / Q000187:drug effects*; D000077291:Terbinafine; D014230:Triazoles / Q000494:pharmacology*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D009281:Naphthalenes; D011743:Pyrimidines; D014230:Triazoles; D000077291:Terbinafine; D065819:Voriconazole