Effect of nikkomycin Z and 50% human serum on the killing activity of high-concentration caspofungin against Candida species using time-kill methodology.
ABSTRACT Caspofungin and nikkomycin Z (NIK) efficacy alone and in combination were tested against seven Candida species showing or not showing paradoxical growth (PG) against caspofungin in time-kill test in RPMI-1640. Selected isolates against caspofungin and NIK were also tested in 50% serum. PG was always eliminated by NIK as well as by serum. In the serum, 1 and 16 μg/ml caspofungin yielded 0.14-4.0 and 0.34-4.0 log CFU decreases from the starting inocula for C. albicans, C. glabrata, C. tropicalis, and C. dubliniensis, respectively. CFU decrease (0.10-2.08 log) at 16 μg/ml, but not at lower caspofungin concentration was noted against C. parapsilosis, C. orthopsilosis, and C. metapsilosis. One C. parapsilosis isolate was not inhibited even by 16 μg/ml caspofungin. Caspofungin against C. albicans, C. glabrata, C. tropicalis, and C. dubliniensis maintained its activity in serum at even 1 μg/ml concentration. PG seems to an in vitro phenomenon, without clinical relevance.
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ABSTRACT: Caspofungin activity was determined in vitro and in vivo against three Candida orthopsilosis, three C. metapsilosis, two C. parapsilosis sensu stricto and two C. albicans isolates. MIC values and killing activity were determined in RPMI-1640 plus 50 % human serum. Neutropenic (cyclophosphamide-treated) mice were infected intravenously. Five-day intraperitoneal treatment with caspofungin was started after 24 h postinfection. Kidney burden was analyzed using the Kruskal-Wallis test with Dunn's post-test. In killing studies, caspofungin was fungistatic and fungicidal against C. albicans at ≥0.25 and ≥2 μg/ml concentrations, respectively. Caspofungin was fungistatic at ≥8-16, ≥2-8 and at ≥2-8 μg/ml against C. parapsilosis, C. orthopsilosis and C. metapsilosis, respectively. In the murine model, C. albicans was inhibited by 1, 2 and 5 mg/kg of caspofungin (P < 0.001 compared to the controls). Against C. parapsilosis, only 5 mg/kg caspofungin was effective against both isolates (P < 0.05). Two and five mg/kg of caspofungin was effective against all C. orthopsilosis and C. metapsilosis isolates (P < 0.05 to <0.001). Serum-based killing tests proved to be useful in predicting in vivo efficacy of caspofungin against four Candida species. Caspofungin at clinically attainable concentrations proved to be effective against all four species.Mycopathologia 05/2012; 174(4):311-8. · 1.65 Impact Factor