Evaluation of the echinocandin antifungal MK-0991 (L-743,872): efficacies in mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis

Abstract

The in vivo activity of the Merck antifungal echinocandin drug candidate MK-0991 (L-743,872) was evaluated in mouse models of disseminated candidiasis, aspergillosis, and cryptococcosis. The echinocandins are potent inhibitors of 1,3-beta-D-glucan synthase. Two models of disseminated candidiasis were used. In a Candida albicans mouse survival model with both DBA/2N and CD-1 mice, estimates of the 50% effective doses (ED50s) of MK-0991 were 0.04 and 0.10 mg/kg of body weight/dose at 21 days after challenge, respectively. In a C. albicans target organ assay (TOA) with DBA/2N mice, MK-0991 at levels of > or =0.09 mg/kg/dose significantly reduced the numbers of C. albicans CFU/g of kidneys compared to the numbers in the kidneys of control mice from 1 to 28 days after challenge. Even when given as a single intraperitoneal dose either 30 min or 24 h after challenge, MK-0991 was effective and significantly reduced the numbers of C. albicans CFU/g of kidney compared to those in the controls. MK-0991 was >300-fold less active when it was administered orally than when it was administered parenterally. MK-0991 was efficacious in mouse TOAs against other C. albicans strains and Candida species including Candida tropicalis, Candida (Torulopsis) glabrata, Candida lusitaniae, Candida parapsilosis, and Candida krusei. MK-0991 was ineffective against disseminated Cryptococcus neoformans infections. In the model of disseminated aspergillosis in mice, MK-0991 at doses of > or =0.02 mg/kg/dose significantly prolonged the survival of DBA/2N mice, with estimates of the ED50 and ED90 of MK-0991 being 0.03 and 0.12 mg/kg/dose, respectively, at 28 days after challenge. MK-0991 is a potent, parenterally administered therapeutic agent against disseminated candidiasis and aspergillosis that warrants further investigation in human clinical trials.

Caspofungin: an advanced treatment approach for suspected or confirmed invasive aspergillosis

“…The in vitro antifungal activity of caspofungin broadly accords with the in vivo data obtained in animal models [52][53][54]; in addition, caspofungin also shows some efficacy in Pneumocystis jiroveci infection in animal models [55].…”

The echinocandin caspofungin impairs the innate immune mechanism against Candida parapsilosis

“…C. parapsilosis tends to be associated with higher minimal inhibitory concentrations (MICs) for caspofungin [19][20][21][22][23][24]. However, caspofungin is generally effective in infections caused by C. parapsilosis [17,18,[25][26][27]. There are minimal data available regarding the development of echinocandin resistance in fungi in the clinical setting.…”

In Vitro Activity of the New Echinocandin Antifungal, MK-0991, against Common and Uncommon Clinical Isolates of Candida Species

“…This class acts by blocking 1-3-b-glucan synthase, thus inhibiting cell wall synthesis. MK-0991 (formerly L-743,872) represents a most promising drug in this class of compounds, having shown excellent in vitro/in vivo activities against the most common species of Candida, several filamentous fungi, the dimorphic pathogen Histoplasma capsulatum, and Pneumocystis carinii [5][6][7][8][9][10][11][12].…”