Comparative in vivo activity of BAL4815, the active component of the prodrug BAL8557, in a neutropenic murine model of disseminated Aspergillus flavus.
BACKGROUND
BAL8557 (WSA) is the water-soluble prodrug of the triazole BAL4815 with in vitro anti-Aspergillus activity. We compared the activity of oral BAL8557 with oral itraconazole, oral voriconazole and intravenous caspofungin in a temporarily neutropenic murine model of disseminated Aspergillus flavus.


METHODS
Mice were immunosuppressed using cyclophosphamide, then infected. Mice were treated either 2 h pre-infection (PRE), or 4 or 24 h post-infection (4POST and 24POST, respectively). Treatment was for 10 days followed by 4 days of observation. Surviving mice were killed and liver, kidneys, lungs and brain cultured. BAL8557 groups included doses corresponding to approximately 30, 15, 6 and 3 mg/kg of the active BAL4815; comparators included itraconazole 25 and 10 mg/kg/dose, voriconazole (plus oral grapefruit) 25 and 10 mg/kg/day or caspofungin 1 mg/kg/day. In a simultaneous tissue burden study mice were treated for 3 days, kidneys removed and homogenized and burden measured by quantitative culture and quantitative PCR using fluorescence resonance energy transfer (FRET).


RESULTS
Control mice had 83-100% mortality. Over 66% of BAL8557-treated mice survived after >6 mg/kg PRE or >15 mg/kg POST. In the PRE models BAL8557 (6 mg/kg) and caspofungin were 100% protective and itraconazole 67% protective, but voriconazole 10 mg/kg had 100% mortality (P = 0.0016). In the 4POST and 24POST models survival was >66% with BAL8557 30 and 15 mg/kg/dose and similar to voriconazole or itraconazole. In the 24POST groups, sterilization of all organs was achieved in 11/16 survivors treated with BAL8557. The quantitative PCR correlated with kidney fungal burden (r2 = 0.59). Earlier treatment reduced burdens.


CONCLUSIONS
BAL8557 demonstrated impressive antifungal activity against A. flavus in this model, in both survival and tissue burden.
Warn
Peter A
PA
School of Medicine, University of Manchester, 1.800 Stopford Building, Oxford Road, Manchester M13 9PT, UK. peter.warn@.manchester.ac.uk
Sharp
Andrew
A
Mosquera
Juan
J
Spickermann
Jochen
J
Schmitt-Hoffmann
Anne
A
Heep
Markus
M
Denning
David W
DW
D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology; D001231:Aspergillus flavus / Q000187:drug effects*; D001921:Brain / Q000382:microbiology; D000077336:Caspofungin; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D054714:Echinocandins; D031541:Fluorescence Resonance Energy Transfer; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D017964:Itraconazole / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007668:Kidney / Q000382:microbiology; D055666:Lipopeptides; D008099:Liver / Q000382:microbiology; D008168:Lung / Q000382:microbiology; D008297:Male; D051379:Mice; D009503:Neutropenia / Q000150:complications*; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D016133:Polymerase Chain Reaction / Q000379:methods; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D016019:Survival Analysis; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D065819:Voriconazole; D011725:Pyridines
D000935:Antifungal Agents; D000077336:Caspofungin; D054714:Echinocandins; D017964:Itraconazole; D055666:Lipopeptides; D009570:Nitriles; D010456:Peptides, Cyclic; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole; C508735:isavuconazole; D011725:Pyridines