Understanding the microbiology of the Aspergillus cell wall and the efficacy of caspofungin

Abstract

The efficacy of echinocandins against Aspergillus species has been established through in vitro assays, in animal models of infection, and in clinical practice. Caspofungin is an inhibitor of 1,3-β-D glucan synthesis (GS) that produces dramatic morphological changes, but incomplete clearing, in cultures of growing hyphae. Despite the apparent fungistatic in vitro activity against Aspergillus species, compounds in this class have strong efficacy in vivo. For example, caspofungin prolonged survival in chronically immunosuppressed mice with induced disseminated aspergillosis, even when neutropenia was maintained for weeks after a short dosing regimen. Kidneys of these mice showed no evidence of recrudescent Aspergilluis fumigatus burden after the infection had been treated. One possible explanation for echinocandin-mediated clearance of A. fumigatus in vivo stems from the newly-discovered role of β-glucan in the inflammatory response. Binding of cell wall β-glucan to the dectin-1 receptor of macrophages leads to production of proinflammatory cytokines, which augment the innate immune response to swollen conidia and germlings. Changes in A. fumigatus cell wall structure, such as those produced by exposure to an echinocandin like caspofungin, may increase the opportunity for interactions between 1,3-β-D glucan and dectin-1, and lead to a heightened response to 'wounded' hyphae.