Preclinical Efficacy of MK-991 in Combination with Amphotericin B or Fluconazole in Mouse Models of Disseminated Aspergillosis, Candidiasis, and Cryptococcisis

A.M. FLATTERY, K. BARTIZOL, C.J. GILL, L. KONG, C. LEIGHTON, V.B. PIKOUNIS, H. ROSEN, J.G. SMITH, and G.K. ABRUZZO

Abstract: 

The in vivo activity of echinocandin MK-0991 (formerly L-743872), an inhibitor of 1,3 beta-D-glucan synthesis, in combination with amphotericin B (AmB) or fluconazole (FCZ) was determined in several mouse models of disseminated fungal disease (aspergillosis, candidiasis, and cryptococcosis). Both C'5-deficient DBA mice and Cytoxan(r)}-induced pancytopenic ICR mice were challenged intravenously (i.v.) with either Candida albicans MY 1055 or conidia of Aspergillus fumigatus MF5668, while only DBA/2N mice were challenged i.v. with Cryptococcus neoformans MY2061. Compounds were administered intraperitoneally. For the disseminated Aspergillus mouse protection models, mortality was monitored following challenge and effective dose (ED) values calculated. In the Candida and Cryptococcus target organ models, efficacy was based on the reduction in cfu/g tissue. When tested in combination in the Candida and Cryptococcus target organ models, there was no evidence of synergy nor antagonism between MK-0991 and FCZ. Combination therapy with MK-0991 and AmB showed no evidence of antagonism in any of the models and no synergy or additive effects vs. C. neoformans. Although no synergy was seen vs. Aspergillus in pancytopenic mice, combinations of MK-0991 at 0.008 mg/kg + AmB at 0.031 mg/kg were synergistic in the DBA/2N model. In the candidiasis model in pancytopenic mice, synergy was observed at two dose concentrations; MK-0991 at 0.03 or 0.06 mg/kg + AmB at 0.016 mg/kg. Lack of antagonism between MK-0991 and AmB or FCZ in mice does not contraindicate concomitant or follow-up clinical use of these agents against life-threatening mycoses.
1998

abstract No: 

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Full conference title: 

38th Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 38th