NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant.

TABLE 9: Acceptable Quality Control Ranges * for Caspofungin to be used in Validation of Susceptibility Test Results  QC strain Broth microdilution

(MIC in μg/mL) at 24-hour
*
Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive interlaboratory variation during initial quality control studies.
†
ATCC is a registered trademark of the American Type Culture Collection. 
Candida parapsilosis ATCC† 22019    0.25 – 1.0
Candida krusei ATCC 6258    0.12 – 1.0

Activity in vivo

Caspofungin was active when parenterally administered to immunocompetent and immunosuppressed mice as long as 24 hours after disseminated infections with C. albicans, in which the endpoints were prolonged survival of infected mice and reduction of C. albicans from target organs. Caspofungin, administered parenterally to immunocompetent and immunosuppressed rodents, as long as 24 hours after disseminated or pulmonary infection with Aspergillus fumigatus, has shown prolonged survival, which has not been consistently associated with a reduction in mycological burden.

Drug Resistance

A caspofungin MIC of ≤2 μg/mL (Susceptible) indicates that the Candida isolate is likely to be inhibited if caspofungin therapeutic concentrations are achieved; there is insufficient treatment outcome information on isolates with reduced caspofungin susceptibility to define categories other than susceptible. Breakthrough infections with Candida isolates requiring caspofungin concentrations >2 μg/mL for growth inhibition have developed in a mouse model of C. albicans infection and in some patients with Candida infections. Some of these isolates had mutations in the FKS1 gene. The incidence of drug resistance by various clinical isolates of Candida and Aspergillus species is unknown.

Drug Interactions

Studies in vitro and in vivo of caspofungin, in combination with amphotericin B, suggest no antagonism of antifungal activity against either A. fumigatus or C. albicans. The clinical significance of these results is unknown.
13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility
No long-term studies in animals have been performed to eva luate the carcinogenic potential of caspofungin.

Caspofungin did not show evidence of mutagenic or genotoxic potential when eva luated in the following in vitro assays: bacterial (Ames) and mammalian cell (V79 Chinese hamster lung fibroblasts) mutagenesis assays, the alkaline elution/rat hepatocyte DNA strand break test, and the chromosome aberration assay in Chinese hamster ovary cells. Caspofungin was not genotoxic when assessed in the mouse bone marrow chromosomal test at doses up to 12.5 mg/kg (equivalent to a human dose of 1 mg/kg based on body surface area comparisons), administered intravenously.