title: Triazole-polyene antagonism in experimental invasive pulmonary aspergillosis: in vitro and in vivo correlation.
abstract: Combination antifungal therapy is increasingly used in the treatment of invasive aspergillosis. Whether the interaction between amphotericin B and triazoles is antagonistic against invasive aspergillosis is a controversial issue that is not likely to be resolved through a randomized clinical trial. Here, we found both in vitro and in vivo antagonism between liposomal amphotericin B and ravuconazole in simultaneous treatment of experimental invasive pulmonary aspergillosis in persistently neutropenic rabbits. Bliss independence-based drug-interaction modeling showed significant antagonism in vitro and in vivo, with the observed drug effects being 20%-69% lower than would be expected if the drugs were acting independently. These in vitro and in vivo findings of antagonism were consistent with the findings from Loewe additivity-based drug-interaction modeling. No pharmacokinetic interaction was found. The combination of a triazole and polyene may be antagonistic in the treatment of invasive pulmonary aspergillosis.
authors.affiliation: Immunocompromised Host Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Meletiadis
authors.forename: Vidmantas
authors.initials: V
authors.lastname: Petraitis
authors.forename: Ruta
authors.initials: R
authors.lastname: Petraitiene
authors.forename: Pengxin
authors.initials: P
authors.lastname: Lin
authors.forename: Theodouli
authors.initials: T
authors.lastname: Stergiopoulou
authors.forename: Amy M
authors.initials: AM
authors.lastname: Kelaher
authors.forename: Tin
authors.initials: T
authors.lastname: Sein
authors.forename: Robert L
authors.initials: RL
authors.lastname: Schaufele
authors.forename: John
authors.initials: J
authors.lastname: Bacher
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
mesh_terms: D000666:Amphotericin B / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use; D001228:Aspergillosis / Q000188:drug therapy*; D001232:Aspergillus fumigatus / Q000187:drug effects*; D004336:Drug Antagonism; D004359:Drug Therapy, Combination; D006801:Humans; D008081:Liposomes / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use; D008172:Lung Diseases, Fungal / Q000188:drug therapy*; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D011090:Polyenes / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D013844:Thiazoles / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use; D014230:Triazoles / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000935:Antifungal Agents; D008081:Liposomes; D011090:Polyenes; D013844:Thiazoles; D014230:Triazoles; C068538:liposomal amphotericin B; D000666:Amphotericin B; C104066:ER 30346