The in vitro activity of caspofungin (CAS) was investigated against 28 yeast isolates belonging to Candida albicans (n ‫؍‬ 5), Candida guilliermondii (n ‫؍‬ 10), and Candida parapsilosis (n ‫؍‬ 13). CAS MICs obtained by broth dilution and Etest methods clearly showed a rank order of susceptibility to the echinocandin compound with C. albicans > C. parapsilosis > C. guilliermondii. Similarly, time-kill assays performed on selected isolates showed that CAS was fungistatic against C. albicans and C. parapsilosis, while it did not exert any activity against C. guilliermondii. In a murine model of systemic candidiasis, CAS given at doses as low as 1 mg/kg of body weight/day was effective at reducing the kidney burden of mice infected with either C. albicans or C. guilliermondii isolates. Depending on the isolate tested, mice infected with C. parapsilosis responded to CAS given at 1 and/or 5 mg/kg/day. However, the overall CFU reduction for C. guilliermondii and C. parapsilosis was approximately 100-fold less than that for C. albicans. Our study shows that CAS was active in experimental systemic candidiasis due to C. guilliermondii and C. parapsilosis, but this activity required relatively high drug dosages.

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 g/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.One of the most desirable properties of a given antimicrobial agent is represented by its ability to "kill" the microorganism. Theoretically, this important characteristic would allow a more rapid and a complete organ clearance during an infection. While for several antibacterial agents activity has been widely documented, among the antifungal agents currently in use in clinical practice only amphotericin B (AMB) is believed to exert a fungicidal activity against many yeasts and filamentous fungi (13). This important property makes this polyene still the mainstay of antifungal therapy for several life-threatening fungal infections.The new echinocandin compound caspofungin (CAS) has the potential for fungicidal activity against Candida spp. and has been shown to be better tolerated than AMB deoxycholate (1,4,5,7,13).Candida glabrata has recently emerged as a significant pathogen, and there are increasing numbers of reports showing its important role in causing either superficial or deep-seated infections (6,8,12,14). Systemic infections due to C. glabrata are characterized by a high mortality rate, and they are difficult to treat due to a reduced susceptibility of this species to azole drugs, especially to fluconazole (12,14). A fungicidal drug for infections due to this emerging pathogen would be beneficial.Therefore, in this study we compared the in vitro and in vivo activities of CAS and AMB against C. glabrata. MATERIALS AND METHODSIsolates. A total of 16 clinical isolates of Candida glabrata were used in this study. The isolates were recovered from the gastrointestinal, respiratory, and urinary tracts; blood; and other sterile body fluid specimens. Each strain represented a unique isolate from a patient. Yeast isolates were identified at the species level by conventional morphological and biochemical methods (9) and stored at Ϫ70°C in 10% glycerol. Before the initiation of the study, yeast isolates were subcultured on antimicrobial-agent-free medium to ensure viability and purity.Drugs. CAS was used as a commercial preparation (Cancidas; Merck Sharp & Dohme) for both in vitro and in vivo experiments. It was dissolved in sterile distilled water and in st...

Candida parapsilosis has emerged as an important nosocomial pathogen. In the present study, a checkerboard broth microdilution method was performed to investigate the in vitro activities of caspofungin (CAS) in combination with amphotericin B (AMB) against three clinical isolates of C. parapsilosis. Although there was a significant reduction of the MIC of one or both drugs used in combination, an indifferent interaction (fractional inhibitory concentration index greater than 0.50 and less than or equal to 4.0) was observed in 100% of cases. This finding was confirmed by killing curve studies. By a disk diffusion assay, the halo diameters produced by antifungal agents in combination were often significantly greater than those produced by each drug alone. Antagonism was never observed. In a murine model of systemic candidiasis, CAS at either 0.25 or 1 mg/kg/day combined with AMB at 1 mg/kg/day was significantly more effective than each single drug at reducing the colony counts in kidneys. Higher doses of the echinocandin (i.e., 5 and 10 mg/kg/day) combined with the polyene did not show any advantage over CAS alone. Overall, our study showed a positive interaction of CAS and AMB against C. parapsilosis.The frequency of invasive mycoses due to opportunistic fungal pathogens has increased dramatically over the past two decades, and now Candida spp. ranks as the fourth most common cause of nosocomial bloodstream infections (20). Although Candida albicans is the organism most often associated with serious fungal infections, other Candida spp. have emerged as clinically important pathogens associated with opportunistic infections (17,20).Candida parapsilosis is the second most frequent yeast species isolated from normally sterile body sites in North America, Europe, and Latin America (12,20). Moreover, studies conducted in the United States showed that C. parapsilosis is the most common non-C. albicans Candida spp. in pediatric patients (17,18,23).Caspofungin (CAS) is an echinocandin antifungal agent that has potent activity against many fungal species, including Candida spp. (13,20,22). Clinical studies have shown that CAS is at least as active as amphotericin B and fluconazole in the treatment of invasive candidiasis (13,20).Amphotericin B (AMB) targets fungal ergosterol, the main component of the fungal cell membrane, while CAS inhibits the synthesis of the fungal cell wall by blocking ␤-1,3-D-glucan (6, 7). Its innovative mechanism of action makes this drug a suitable candidate for antifungal combination therapy.Although CAS MICs for C. parapsilosis can be higher than those seen for C. albicans, the echinocandin is generally effective in infections caused by this yeast species (1, 4, 6-8, 13, 20, 22). Similarly, amphotericin B is active in vitro and in vivo against C. parapsilosis (20).In this study, we hypothesized that the combination of CAS and AMB could be advantageous over each monotherapy against C. parapsilosis. To investigate this interaction, we applied in vitro methods and an experimental mouse model of ...

We investigated the in vitro activities of posaconazole (POS), fluconazole (FLC), amphotericin B (AMB), and caspofungin (CAS) against four clinical isolates of Candida glabrata with various susceptibilities to FLC (FLC MICs ranging from 1.0 to >64 g/ml). POS MICs ranged from <0.03 to 0.5 g/ml; AMB MICs ranged from 0.25 to 2.0 g/ml, while CAS MICs ranged from 0.03 to 0.25 g/ml. When FLC MICs increased, so did POS MICs, although we did not observe any isolate with a POS MIC greater than 0.5 g/ml. Time-kill experiments showed that POS, FLC, and CAS were fungistatic against all isolates, while AMB at eight times the MIC was fungicidal against three out of four isolates of C. glabrata tested. Then, we investigated the activity of POS in an experimental model of disseminated candidiasis using three different isolates of C. glabrata: one susceptible to FLC (S; FLC MICs ranging from 1.0 to 4.0 g/ml; POS MIC of <0.03 g/ml), one susceptible in a dose-dependent manner (SDD; FLC MICs ranging from 32 to 64 g/ml; POS MICs ranging from 0.125 to 0.25 g/ml), and another one resistant to FLC (R; FLC MIC of >64 g/ml; POS MIC of 0.5 g/ml). FLC significantly reduced the kidney burden of mice infected with the S strain (P ‫؍‬ 0.0070) but not of those infected with the S-DD and R strains. POS was significantly effective against all three isolates at reducing the kidney fungal burden with respect to the controls (P ranging from 0.0003 to 0.029). In conclusion, our data suggest that POS may be a useful option in the management of systemic infections caused by C. glabrata. Additionally, the new triazole may be a therapeutic option in those cases where an FLC-resistant isolate is found to retain a relatively low POS MIC.

The in vitro activity of fluconazole was investigated against 476 yeast isolates collected during a 9-year period (1997-2005) from patients hospitalised in a teaching hospital of Ancona. They included 373 isolates of Candida albicans, 53 of Candida glabrata and 50 of Candida parapsilosis. Minimum inhibitory concentrations (MICs) determined in accordance with the Clinical Laboratory Standards Institute methodology showed that 96% of the isolates were susceptible (MIC < or =8.0 microg/ml). The uncommon, resistant isolates (MIC > or =64 microg/ml) were randomly distributed over time. Our data show that resistance to fluconazole in this geographical area is a rare event and suggest that this triazole can still represent first-line therapy in our institution.