Posaconazole activity against Candida glabrata after exposure to caspofungin or amphotericin B

Abstract

We evaluated the effects of sequential therapy with caspofungin (CAS) or amphotericin B (AMB) followed by posaconazole (POS) against Candida glabrata. The susceptibilities to POS of yeast cells pre-exposed to CAS or AMB were identical to those of untreated cells as shown by standard Clinical and Laboratory Standards Institute broth dilution, cell viability, and disk diffusion methods. We then investigated the activity of sequential regimens in an experimental model of disseminated candidiasis. CAS given at 1 mg/kg/day for 2 days followed by POS at either 15 or 30 mg/kg/day significantly reduced the counts compared to the controls, but this treatment was not superior to the use of CAS alone. Also, sequential regimens with AMB given at 1 mg/kg/day for 2 days followed by POS (AMB/POS) were effective at reducing the fungal burden against the controls. In addition, AMB/POS with both doses of the triazole were significantly more effective than AMB alone. Overall, our data showed that there is no therapeutic advantage in using CAS followed by POS, whereas an induction therapy with AMB followed by a maintenance regimen with POS might be a suitable strategy in managing C. glabrata infections.

FIG. 1.

Effects of posaconazole on the viability of C. glabrata 4293 grown overnight in drug-free RPMI 1640 medium (□) or medium containing caspofungin (░⃞) or amphotericin B (▪) at one-half the MIC (0.015 and 0.25 μg/ml, respectively). Experiments were performed with an initial inoculum that ranged from 0.5 × 10³ to 2.5 × 10³ CFU/ml. POS MICs were determined according to the CLSI method against either exposed or unexposed cells. The number of CFU per milliliter was determined by plating the wells containing POS at 2× and 16× the MIC (0.5 and 4.0 μg/ml, respectively). The data are averages of the percentage of viable cells at 48 h with respect to the controls, and error bars denote the standard deviations.

FIG. 2.

Tissue burden of kidneys of CD1 mice infected intravenously with C. glabrata 4239 and treated with P (sterile saline solution) from day 1 to day 2 postinfection (P3), CAS from day 1 to day 2 (CAS), AMB from day 1 to day 2 (AMB), P from day 1 to day 6 (P7; sterile saline solution from day 1 to day 2 and PEG-200 from day 3 to day 6), P (sterile saline solution) from day 1 to day 2 followed by POS from day 3 to day 6 (P/POS), CAS from day 1 to day 2 followed by P (PEG-200) from day 3 to day 6 (CAS/P), CAS from day 1 to day 2 followed by POS from day 3 to day 6 (CAS/POS), AMB from day 1 to day 2 followed by P (PEG-200) from day 3 to day 6 (AMB/P), or AMB from day 1 to day 2 followed by POS from day 3 to day 6 (AMB/POS). The first three groups were sacrificed on day 3 postinfection. The last six groups were sacrificed on day 7 postinfection. In study 1, the animals were infected with 1.04 × 10⁸ CFU/mouse and POS was administered at 15 mg/kg/day (A), while in study 2 the animals were challenged with 1.04 × 10⁸ CFU/mouse and POS was administered at 30 mg/kg/day (B). The bars represent the medians. There were seven to eight animals in each group.