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Hexadecylphosphocholine (Miltefosine) Has Broad-Spectrum Fungicidal Activity and Is Efficacious in a Mouse Model of Cryptococcosis

Centre for Infectious Diseases and Microbiology, University of Sydney at Westmead, and Department of Infectious Diseases, ICPMR Building, Westmead Hospital, Westmead, NSW 2145,¹ Centre for Clinical Research Excellence in Infections & Bioethics in Haematological Malignancies, University of Sydney, Sydney, NSW 2006,² Women's and Children's Hospital, North Adelaide, South Australia 5006, Australia³

Received 18 May 2005/ Returned for modification 30 July 2005/ Accepted 31 October 2005

The alkyl phosphocholine drug miltefosine is structurally similar to natural substrates of the fungal virulence determinant phospholipase B1 (PLB1), which is a potential drug target. We determined the MICs of miltefosine against key fungal pathogens, correlated antifungal activity with inhibition of the PLB1 activities (PLB, lysophospholipase [LPL], and lysophospholipase-transacylase [LPTA]), and investigated its efficacy in a mouse model of disseminated cryptococcosis. Miltefosine inhibited secreted cryptococcal LPTA activity by 35% at the subhemolytic concentration of 25 µM (10.2 µg/ml) and was inactive against mammalian pancreatic phospholipase A2 (PLA₂). At 250 µM, cytosolic PLB, LPL, and LPTA activities were inhibited by 25%, 51%, and 77%, respectively. The MICs at which 90% of isolates were inhibited (MIC₉₀s) against Candida albicans, Candida glabrata, Candida krusei, Cryptococcus neoformans, Cryptococcus gattii, Aspergillus fumigatus, Fusarium solani, Scedosporium prolificans, and Scedosporium apiospermum were 2 to 4 µg/ml. The MICs of miltefosine against Candida tropicalis (n = 8) were 2 to 4 µg/ml, those against Aspergillus terreus and Candida parapsilosis were 8 µg/ml (MIC₉₀), and those against Aspergillus flavus (n = 8) were 2 to 16 µg/ml. Miltefosine was fungicidal for C. neoformans, with rates of killing of 2 log units within 4 h at 7.0 µM (2.8 µg/ml). Miltefosine given orally to mice on days 1 to 5 after intravenous infection with C. neoformans delayed the development of illness and mortality and significantly reduced the brain cryptococcal burden. We conclude that miltefosine has broad-spectrum antifungal activity and is active in vivo in a mouse model of disseminated cryptococcosis. The relatively small inhibitory effect on PLB1 enzyme activities at concentrations exceeding the MIC by 2 to 20 times suggests that PLB1 inhibition is not the only mechanism of the antifungal effect.

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