title: In vitro activity of a new triazole BAL4815, the active component of BAL8557 (the water-soluble prodrug), against Aspergillus spp.
abstract: OBJECTIVE
  BAL4815 is the active component of the antifungal triazole agent BAL8557 (the water-soluble prodrug). We compared the in vitro activity of BAL4815 with that of itraconazole, voriconazole, caspofungin and amphotericin B against 118 isolates of Aspergillus comprising four different species (fumigatus, terreus, flavus and niger); the isolates were pre-selected to include 16 isolates demonstrating in vitro resistance to other agents.
  
  
  METHODS
  Susceptibilities were determined for BAL4815, amphotericin B, itraconazole and voriconazole using the microdilution plate modification of the NCCLS M38-A method with RPMI 1640 buffered to pH 7.0 with MOPS; for caspofungin the method was modified using incubation in a gas mixture of 1% O2/5% CO2/94% N2 to aid reading. MFCs (> or =99% kill) were also determined for all drugs other than caspofungin.
  
  
  RESULTS
  For all isolates, geometric mean (GM) MIC values and ranges (in mg/L) were: BAL4815, 0.620 and 0.125-2.0; itraconazole, 0.399 and 0.063->8.0; voriconazole, 0.347 and 0.125-8.0; caspofungin, 0.341 and 0.125-4.0; amphotericin B, 0.452 and 0.06-4.0. No significant differences in susceptibility to BAL4815 were seen between species and in contrast to itraconazole no isolates demonstrated MICs >2.0 mg/L. For all isolates, GM MFC values and ranges (in mg/L) were: BAL4815, 1.68 and 0.25->8.0; itraconazole, 1.78 and 0.06->8.0; voriconazole, 1.09 and 0.25->8.0; amphotericin B, 0.98 and 0.25->4.0.
  
  
  CONCLUSIONS
  BAL4815 demonstrated promising antifungal activity against all four Aspergillus species in vitro including strains resistant to itraconazole, caspofungin or amphotericin B.
authors.affiliation: School of Medicine, 1.800 Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK. peter.warn@manchester.ac.uk
authors.forename: Peter A
authors.initials: PA
authors.lastname: Warn
authors.forename: Andrew
authors.initials: A
authors.lastname: Sharp
authors.forename: David W
authors.initials: DW
authors.lastname: Denning
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D001230:Aspergillus / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification; D025141:Drug Resistance, Fungal / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D014867:Water
chemical_list: D000935:Antifungal Agents; D009570:Nitriles; D011355:Prodrugs; D011725:Pyridines; D014230:Triazoles; D014867:Water; C508735:isavuconazole