Comparative Effects of Micafungin, Caspofungin, and Anidulafungin against a Difficult-To-Treat Fungal Opportunistic Pathogen, Candida glabrata

Abstract

The aim of this study was to compare the in vitro and in vivo activities of micafungin, caspofungin, and anidulafungin against Candida glabrata. The MICs against 28 clinical isolates showed that the overall susceptibilities to caspofungin and to micafungin were not statistically different in the absence of human serum, whereas the isolates were less susceptible to micafungin than to caspofungin in its presence. Minimum fungicidal concentrations, as well as time-kill experiments, showed that caspofungin was more active than anidulafungin, while micafungin was superior to either caspofungin or anidulafungin without serum; its addition rendered caspofungin and micafungin equally effective. A murine model of systemic candidiasis against a C. glabratasusceptible isolate was performed to study the effects of all three echinocandins, and kidney burden counts showed that caspofungin, micafungin, and anidulafungin were active starting from 0.25, 1, and 5 mg/kg of body weight/day, respectively. Two echinocandin-resistant strains of C. glabrata were selected: C. glabrata 30, a laboratory strain harboring the mutation Fks2p-P667T, and C. glabrata 51, a clinical isolate harboring the mutation Fks2p-D666G. Micafungin activity was shown to be as effective as or more effective than that of caspofungin or anidulafungin in terms of MICs. In vivo studies against these resistant strains showed that micafungin was active starting from 1 mg/kg/day, while caspofungin was effective only when administrated at higher doses of 5 or 10 mg/kg/day. Although a trend toward colony reduction was observed with the highest doses of anidulafungin, a significant statistical difference was never reached. Candida glabrata has recently been reported to be the second most common cause of invasive candidiasis, and there are increasing amounts of data showing its important role in determining either superficial or deep-seated infections (4, 18). Systemic infections due to C. glabrata are characterized by a high mortality rate, and they are difficult to treat due to reduced susceptibility of the species to azole drugs, especially to fluconazole (26). According to the published guidelines, amphotericin B can be used to treat infections due to C. glabrata, especially in profoundly immunocompromised hosts (22). Fortunately, the species also appears to be highly susceptible to the echinocandins (i.e., caspofungin, anidulafungin, and micafungin), making these agents valuable alternatives as first-line therapy against this Candida species (22). Interestingly, patients suffering from systemic candidiasis due to C. glabrata showed a trend, although not a significant one, to a better clinical outcome when treated with micafungin (87%) rather than with caspofungin (67%) (23).The three echinocandin antifungal agents anidulafungin, caspofungin, and micafungin have a unique mechanism of action, inhibiting ␤-1,3-D-glucan synthase, an enzyme that is necessary for the synthesis of ␤-1,3-D-glucan polymers, essential components of the cell walls of several fungi (8).Althou...

Dose escalation studies with caspofungin against Candida glabrata

“…In agreement with other studies (Andes et al, 2010;Fernández-Silva et al, 2014;Gil-Alonso et al, 2015;Lepak et al, 2012;Pfaller et al, 2011;Spreghini et al, 2012;Szilágyi et al, 2012), caspofungin showed excellent in vitro activity against WT clinical isolates as well as against the ATCC 90030 type strain. However, in RPMI 1640, caspofungin killing activity decreased at 16-32 mg l 21 when compared with the killing at 0.25-1 mg l 21 (Table 3).…”

“…In accordance with other authors (Andes et al, 2010;Fernández-Silva et al, 2014;Lepak et al, 2012;Spreghini et al, 2012;Wiederhold et al, 2007), WT C. glabrata clinical isolates were highly susceptible in vivo to caspofungin even at 1 mg kg 21 in mice (corresponding to a 35 mg daily dose in humans) (Cornely et al, 2011;Flattery et al, 2011;Migoya et al, 2011). Moreover, as observed previously with Candida albicans, Candida krusei and Candida inconspicua, increasing the drug dose further did not yield better efficacy (Berényi et al, 2014;Kovács et al, 2014a), i.e.…”

“…to allow the fungi to establish tissue infection (Berényi et al, 2014;Földi et al, 2012b;Kovács et al, 2014a, Spreghini et al, 2012Wiederhold et al, 2007). This dosing strategy was based on previous pharmacokinetic studies (Andes et al, 2010;Cornely et al, 2011;Flattery et al, 2011;Migoya et al, 2011;Stone et al, 2002), on previous results from our study group (Berényi et al, 2014;Földi et al, 2012b;Kovács et al, 2014a) and on the findings of Howard et al (2011) At the beginning of therapy (day 1), the fungal kidney burden was determined after dissection of four untreated mice for each isolate (day 1 control burden) (Berényi et al, 2014).…”

“…(g tissue) 21 . The kidney burden was analysed using the Kruskal-Wallis test with Dunn's post-test for multiple comparisons (Berényi et al, 2014;Földi et al, 2012b;Kovács et al, 2014a, Spreghini et al, 2012Wiederhold et al, 2007).…”

Biguanides enhance antifungal activity against Candida glabrata

“…The current first-line treatment for candidemia due to C. glabrata are echinocandin agents, such as micafungin, which are potent inhibitors of beta-glucan synthase, a critical component of the fungal cell wall [1,9]. Echinocandins are efficacious against fluconazole-resistant Candida species, however, during prolonged therapy, C. glabrata can develop reduced susceptibility even to this class [10]. C. glabrata echinocandin resistance has increased from 4.9 to 12.3% between 2001 and 2010, and among the fluconazole-resistant isolates tested, 14.1% were fluconazole/echinocandin double-resistant [11].…”