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

Antimicrob Agents Chemother. 1997 Nov;41(11):2333-8. doi: 10.1128/AAC.41.11.2333.

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.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Bacterial Agents / therapeutic use*
  • Antifungal Agents / therapeutic use*
  • Aspergillosis / drug therapy*
  • Candidiasis / drug therapy*
  • Caspofungin
  • Cryptococcosis / drug therapy*
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Echinocandins
  • Female
  • Injections, Intraperitoneal
  • Kidney Diseases / drug therapy
  • Lipopeptides
  • Mice
  • Mice, Inbred DBA
  • Peptides*
  • Peptides, Cyclic*

Substances

  • Anti-Bacterial Agents
  • Antifungal Agents
  • Echinocandins
  • Lipopeptides
  • Peptides
  • Peptides, Cyclic
  • Caspofungin