title: The concentration-dependent nature of in vitro amphotericin B-itraconazole interaction against Aspergillus fumigatus: isobolographic and response surface analysis of complex pharmacodynamic interactions.
abstract: The interaction between polyenes and azoles is not well understood. We therefore explored the in vitro combination of amphotericin B with itraconazole against 14 clinical Aspergillus fumigatus isolates (9 itraconazole susceptible and 5 itraconazole resistant) with a colorimetric broth microdilution checkerboard technique using two drug interaction models able to explore complicated patterns of interactions: the response surface analysis of Bliss independence and the isobolographic analysis of Loewe additivity zero interaction theories. Synergy was found at combinations with low concentrations of amphotericin B (<0.125 mg/L), whereas antagonism was found at combinations with higher concentrations of amphotericin B. For itraconazole-resistant isolates, synergistic interactions were observed at high concentrations of itraconazole (>0.5 mg/L). Synergy was more frequently observed for the itraconazole-resistant isolates than for the itraconazole-susceptible isolates.
authors.affiliation: National Cancer Institute, Pediatric Oncology Branch, Bethesda, MD 20892, USA. meletiaj@mail.nih.gov
authors.forename: Joseph
authors.initials: J
authors.lastname: Meletiadis
authors.forename: Debbie T A
authors.initials: DT
authors.lastname: te Dorsthorst
authors.forename: Paul E
authors.initials: PE
authors.lastname: Verweij
mesh_terms: D000465:Algorithms; D000666:Amphotericin B / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004347:Drug Interactions; D025141:Drug Resistance, Fungal; D004357:Drug Synergism; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008954:Models, Biological
chemical_list: D017964:Itraconazole; D000666:Amphotericin B