In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872)

Abstract

The echinocandin MK-0991, formerly L-743,872, is a water-soluble lipopeptide that has been demonstrated in preclinical studies to have potent activity against Candida spp., Aspergillus fumigatus, and Pneumocystis carinii. An extensive in vitro biological evaluation of MK-0991 was performed to better define the potential activities of this novel compound. Susceptibility testing with MK-0991 against approximately 200 clinical isolates of Candida, Cryptococcus neoformans, and Aspergillus isolates was conducted to determine MICs and minimum fungicidal concentrations MF(s). The MFC at which 90% of isolates are inhibited for 40 C. albicans clinical isolates was 0.5 microg/ml. Susceptibility testing with panels of antifungal agent-resistant species of Candida and C. neoformans isolates indicated that the MK-0991 MFCs for these isolates are comparable to those obtained for susceptible isolates. Growth kinetic studies of MK-0991 against Candida albicans and Candida tropicalis isolates showed that the compound exhibited fungicidal activity (i.e., a 99% reduction in viability) within 3 to 7 h at concentrations ranging from 0.06 to 1 microg/ml (0.25 to 4 times the MIC). Drug combination studies with MK-0991 plus amphotericin B found that this combination was not antagonistic against C. albicans, C. neoformans, or A. fumigatus in vitro. Studies with 0 to 50% pooled human or mouse serum established that fungal susceptibility to MK-0991 was not significantly influenced by the presence of human or mouse serum. Results from resistance induction studies suggested that the susceptibility of C. albicans was not altered by repeated exposure (40 passages) to MK-0991. Erythrocyte hemolysis studies with MK-0991 with washed and unwashed human or mouse erythrocytes indicated minimal hemolytic potential with this compound. These favorable results of preclinical studies support further studies with MK-0991 with humans.

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

“…In general, our MK-0991 MICs agreed with those previously reported by other authors [7,12]. We have found that 100% of the isolates were inhibited by MK-0991 at a concentration of 0.78 mg/ml or less and that fungicidal activity was exerted at a concentration of 1.5 mg/ml or less for 73% of the isolates tested.…”

“…Contrary to that reported by Vazquez et al [12], we found fungicidal activity against Candida lusitaniae and Candida krusei (geometric mean MFCs of 0.65 mg/ml and 0.78 mg/ml, respectively) and poor fungicidal activity against Candida parapsilosis (geometric mean MFC of 6.24 mg/ml). Our data confirmed limited fungicidal activity of the new echinocandin against Candida guilliermondii [7,12]. In addition, we observed the same phenomenon for Candida famata.…”

“…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].…”

What’s new in antifungals?

“…The agent has shown activity in vitro and in animal models against a variety of fungal pathogens. The activity of caspofungin against Aspergillus species and Candida species has been extensively evaluated in vitro, and is also supported by animal model studies [18][19][20][21][22][23][24][25][26][27]. Initial preclinical studies showed that caspofungin had limited activity against C. neoformans, however, there is evidence that caspofungin may enhance the activity of amphotericin B against this pathogen [28,29].…”

Antifungal antibiotics

“…They are mainly used topically in the treatment of candidiasis, coccidiodal meningitis, cutaneous dermatophytes and histoplasmosis (Iyer 1998). The echinocandins (glucan synthesis inhibitors) and nikkomycins (chitin synthesis inhibitors) are used in combination with amphotericin B and have relatively lower toxicity, compared with the polyenes (Decker et al 1990(Decker et al , 1991Bartizal et al 1997). Thus, a number of factors affect and limit the use of some of the existing antifungal antibiotics, which necessitates a search for newer antifungal antibiotics to control existing problems.…”