Comparison of the fungicidal activities of caspofungin and amphotericin B against Candida glabrata

Abstract

We investigated the fungicidal activity of caspofungin (CAS) and amphotericin B (AMB) against 16 clinical isolates of Candida glabrata. The minimum fungicidal concentrations (MFCs) of CAS were similar to those of AMB, ranging from 2.0 to >8.0 microg/ml. Time-kill assays performed on selected isolates showed that AMB was fungicidal at concentrations four times the MIC while CAS was not. A neutropenic-mouse model of disseminated infection was utilized to determine the residual fungal kidney burden. While doses as low as 0.3 and 1 mg/kg of body weight/day of CAS and AMB, respectively, were effective at reducing the counts with respect to controls, organ sterilization was reached when both drugs were administered at 5 mg/kg/day. Our study reveals that, similar to AMB, CAS has the potential for a fungicidal effect in vivo against this difficult-to-treat fungal pathogen.

FIG. 1.

CAS (white bars) and AMB (black bars) MICs (A) and MFCs (B) of 16 clinical isolates of Candida glabrata.

FIG. 2.

Time-kill studies conducted with C. glabrata 4205 and C. glabrata 4293. The solid lines represent a >99.9% growth reduction compared with the initial inoculum size (fungicidal effect). The limit of detection (20 CFU/ml) is represented by the dotted lines. Each data point represents the mean ± standard deviation for three independent experiments.

FIG. 3.

Kidney tissue burden of neutropenic CD1 mice. For study no. 1 (A and B), the mice were infected intravenously with 1.2 × 10⁸ CFU/mouse of C. glabrata 4293 and treated daily with CAS at 0.3 or at 1 mg/kg/day (CAS 0.3 and CAS 1) and with AMB at 0.3 or at 1 mg/kg/day (AMB 0.3 and AMB 1). For study no. 2 (C and D), the mice were infected intravenously with 2.6 × 10⁸ CFU/mouse and treated daily with CAS at 3 or 5 mg/kg/day (CAS 3 and CAS 5) and with AMB at 3 or 5 mg/kg/day (AMB 3 and AMB 5). Tissue burden experiments for control mice (C) were performed on days 1, 3, 5, and 7 postinfection. Tissue burden experiments for treated mice were performed on days 3, 5, and 7 postinfection, which corresponded to a total of 2, 4, and 6 days of therapy, respectively. The bars represent the medians. The asterisks at the bottom of panels A, B, C, and D indicate P values of <0.025.