The interaction of human monocytes, monocyte-derived macrophages, and polymorphonuclear neutrophils with caspofungin (MK-0991), an echinocandin, for antifungal activity against Aspergillus fumigatus.
The collaboration between human effector cells and caspofungin (MK-0991), a 1,3-beta-D glucan synthase inhibitor, was studied for antifungal activity against Aspergillus fumigatus. Caspofungin was co-cultured for 24h with either human monocytes (Monos), monocyte-derived macrophages (MDM), or polymorphonuclear neutrophils (PMN) against germlings of A. fumigatus and antifungal activity assessed using the XTT metabolic assay. Caspofungin at 0.1 micorg/ml and 0.05 microg/ml or Monos alone against germlings caused significant inhibition. Microscopically this was correlated with less growth and stunted malformed hyphae. The addition of caspofungin at 0.1 microg/ml and 0.05 microg/ml to the monocyte cultures increased antifungal activity. The inhibition of the combination was significantly greater than drug alone (P <.01) and Monos alone (P <.01). MDM against Aspergillus germlings inhibited hyphal growth. The combination of caspofungin at 0.1 microg/ml and 0.05 microg/ml to the macrophage cultures increased antifungal activity. The growth inhibition by the combination was significantly greater than drug alone (P <.01) and MDM alone (P <.01). There was no significant interference with or enhancement of PMNs and caspofungin. These data support the activity of caspofungin against A. fumigatus in vitro, and indicates a cooperative activity with human effector cells. This suggests caspofungin in vivo would have increased efficacy as it combines with host defenses against A. fumigatus.
Division of Infectious Diseases, Department of Medicine, Santa Clara Valley Medical Center, San Jose, CA, USA. chiller@ieland.stanford.edu
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Farrokhshad
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Brummer
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Stevens
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology; D001228:Aspergillosis / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology*; D006801:Humans; D008264:Macrophages / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D010455:Peptides
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D010455:Peptides