Killing rates exerted by caspofungin in 50 % serum and its correlation with in vivo efficacy in a neutropenic murine model against Candida krusei and Candida inconspicua

Abstract

Killing rates (K) of 1-32 µg ml(-1) caspofungin were determined in RPMI-1640 and in 50 % serum using time-kill methodology against three Candida krusei (MICs of all three isolates 0.25 µg ml(-1) in RPMI-1640 and 2 µg ml(-1) in serum) and three Candida inconspicua clinical isolates (MIC ranges 0.06-0.12 µg ml(-1) in RPMI-1640 and 0.25-0.5 µg ml(-1) in serum), against C. krusei ATCC 6258 and against one C. krusei isolate that was resistant to echinocandins (MIC 8 µg ml(-1) in RPMI-1640 and 32 µg ml(-1) in serum). In RPMI-1640, the highest mean K values were observed at 4 (-1.05 h(-1)) and 16 (-0.27 h(-1)) μg ml(-1) caspofungin for C. krusei and C. inconspicua clinical isolates, respectively. In 50 % serum, mean K value ranges at 1-32 and 4-32 µg ml(-1) concentrations for C. inconspicua and C. krusei were -1.12 to -1.44 and -0.42 to -0.57 h(-1), respectively. While K values against C. krusei in RPMI-1640 and 50 % serum were comparable, serum significantly increased the killing rate against C. inconspicua (P<0.0003 for all tested concentrations). In a neutropenic murine model, daily caspofungin at 1, 2, 3, 5 and 15 mg kg(-1) significantly decreased the fungal tissue burden of C. inconspicua in the kidneys (P<0.05-0.001). Against C. krusei, doses of 3, 5 and 15 mg kg(-1) caspofungin were effective (P<0.05-0.01). All effective doses were comparably efficacious for both species. Only the highest 15 mg kg(-1) caspofungin dose was effective even against the echinocandin-resistant C. krusei isolate. In 50 % serum, killing was concentration independent at effective concentrations (≥4 and ≥1 µg ml(-1) for C. krusei and C. inconspicua, respectively), suggesting that the efficacy of dose escalation is questionable. These in vitro results were also supported by the murine model.