Activity of aminocandin (IP960) compared with amphotericin B and fluconazole in a neutropenic murine model of disseminated infection caused by a fluconazole-resistant strain of Candida tropicalis.
OBJECTIVE
To compare the activity of aminocandin (IP960), a new echinocandin with broad-spectrum in vitro activity against Aspergillus and Candida spp., with that of amphotericin B and fluconazole in a temporarily immunocompromised murine model of disseminated candidiasis.


METHODS
Mice were rendered neutropenic with cyclophosphamide and infected intravenously 3 days later with a fluconazole-resistant Candida tropicalis strain. Mice were treated with intraperitoneal amphotericin B (5 mg/kg/dose), oral fluconazole (50 mg/kg/dose), intravenous aminocandin (0.1--5 mg/kg/dose) or solvent control for 9 days. Mice were observed for survival and survivors were sacrificed 11 days post-infection. Kidneys, liver, brain and lungs were removed for semi-quantitative culture.


RESULTS
Control mice had 90--100% mortality. After infection with C. tropicalis, aminocandin 2.5 and 5 mg/kg/day and amphotericin B yielded 80% survival; aminocandin 1 mg/kg/day yielded 70% survival; aminocandin 0.25 and 0.1 mg/kg/day yielded 30% and 20% survival, respectively; and fluconazole 50 mg/kg/day and control regimens yielded 10% and 0--10% survival, respectively. Aminocandin 2.5 and 5.0 mg/kg/day and amphotericin B were superior in reducing mortality compared with aminocandin 0.25 and 0.1 mg/kg/day, fluconazole and controls (P<0.047). The only regimen to reduce organ burdens below detectable levels was amphotericin B, which cleared 40% of mice. All organ burdens in the aminocandin 1.0, 2.5 and 5.0 mg/kg/day and amphotericin B regimens were significantly lower than other groups (P<0.02).


CONCLUSIONS
The data demonstrate that aminocandin at doses of >or=1.0 mg/kg/day is as effective as amphotericin B at improving survival and reducing organ burdens in this murine model of disseminated C. tropicalis.
Warn
Peter A
PA
School of Medicine, 1.800 Stopford Building, University of Manchester, Manchester M13 9PT, UK. Peter.Warn@manchester.ac.uk
Sharp
Andrew
A
Morrissey
Graham
G
Denning
David W
DW
D000666:Amphotericin B / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D041022:Candida tropicalis / Q000187:drug effects* / Q000472:pathogenicity; D002177:Candidiasis / Q000188:drug therapy* / Q000209:etiology / Q000382:microbiology / Q000401:mortality; D003520:Cyclophosphamide / Q000633:toxicity; D004195:Disease Models, Animal; D025141:Drug Resistance, Fungal; D015725:Fluconazole / Q000008:administration & dosage / Q000494:pharmacology*; D016867:Immunocompromised Host; D055666:Lipopeptides; D008074:Lipoproteins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009503:Neutropenia / Q000139:chemically induced / Q000150:complications; D015996:Survival Rate; D016896:Treatment Outcome
D000935:Antifungal Agents; D055666:Lipopeptides; D008074:Lipoproteins; C476911:aminocandin; D000666:Amphotericin B; D003520:Cyclophosphamide; D015725:Fluconazole