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Antimicrob Agents Chemother. Limited Activity of Miltefosine in Murine Models of Cryptococcal Meningoencephalitis and Disseminated Cryptococcosis
[Source: Antimicrobial Agents and Chemotherapy, full text: (LINK). Abstract, edited.]
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Limited Activity of Miltefosine in Murine Models of Cryptococcal Meningoencephalitis and Disseminated Cryptococcosis
Nathan P. Wiederhold 1,2↴, Laura K. Najvar 1,3, Rosie Bocanegra 1,3, William R. Kirkpatrick 1,3, Tania C. Sorrell 4,5,6 and Thomas F. Patterson 1,3
Author Affiliations: <SUP>1</SUP>University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; <SUP>2</SUP>University of Texas at Austin College of Pharmacy, Austin, TX, USA; <SUP>3</SUP>South Texas Veterans Health Care Administration, San Antonio, TX, USA; <SUP>4</SUP>Sydney Emerging Infections and Biosecurity Institute, Sydney, Australia; <SUP>5</SUP>University of Sydney, Sydney, Australia; <SUP>6</SUP>Westmead Millennium Institute, Sydney, Australia
ABSTRACT
Miltefosine is an alkyl phosphocholine with good oral bioavailability and in vitro activity against Cryptococcus species that has gained interest as an additional agent for cryptococcal infections. Our objective was to further evaluate the in vivo efficacy of miltefosine in experimental in vivo models of cryptococcal meningoencephalitis and disseminated cryptococcosis. Mice were infected intracranially or intravenously with either C. neoformans USC1597 or H99. Miltefosine treatment (1.8 ? 45 mg/kg orally once daily) began either 1 hour or 1 day post-inoculation. Fluconazole (10 mg/kg orally twice daily) or amphotericin B deoxycholate (3 mg/kg intraperitoneally once daily) served as positive controls. In our standard models, miltefosine did not result in significant improvements in survival or reductions in fungal burden against either C. neoformans isolate. There was a trend towards improved survival with miltefosine 7.2 mg/kg against disseminated cryptococcosis with the H99 strain, but only at a low infecting inoculum. In contrast, both fluconazole and amphotericin B significantly improved survival in mice with cryptococcal meningoencephalitis and disseminated cryptococcosis due to USC1597. Amphotericin B also improved survival against both cryptococcal infections caused by H99. Combination therapy with miltefosine demonstrated neither synergy nor antagonism in both models. These results demonstrate limited efficacy of miltefosine and suggest caution with the potential use of this agent for the treatment of C. neoformans infections.
FOOTNOTES
Corresponding Author: Nathan P. Wiederhold, Pharm.D., UTHSCSA, PERC MSC 6220, 7703 Floyd Curl Drive, San Antonio, TX 78229, Phone: 210-567-8340, Fax: 210-567-8328, Email: wiederholdn@uthscsa.edu
Copyright ? 2012, American Society for Microbiology. All Rights Reserved.
-Author Affiliations: <SUP>1</SUP>University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; <SUP>2</SUP>University of Texas at Austin College of Pharmacy, Austin, TX, USA; <SUP>3</SUP>South Texas Veterans Health Care Administration, San Antonio, TX, USA; <SUP>4</SUP>Sydney Emerging Infections and Biosecurity Institute, Sydney, Australia; <SUP>5</SUP>University of Sydney, Sydney, Australia; <SUP>6</SUP>Westmead Millennium Institute, Sydney, Australia
ABSTRACT
Miltefosine is an alkyl phosphocholine with good oral bioavailability and in vitro activity against Cryptococcus species that has gained interest as an additional agent for cryptococcal infections. Our objective was to further evaluate the in vivo efficacy of miltefosine in experimental in vivo models of cryptococcal meningoencephalitis and disseminated cryptococcosis. Mice were infected intracranially or intravenously with either C. neoformans USC1597 or H99. Miltefosine treatment (1.8 ? 45 mg/kg orally once daily) began either 1 hour or 1 day post-inoculation. Fluconazole (10 mg/kg orally twice daily) or amphotericin B deoxycholate (3 mg/kg intraperitoneally once daily) served as positive controls. In our standard models, miltefosine did not result in significant improvements in survival or reductions in fungal burden against either C. neoformans isolate. There was a trend towards improved survival with miltefosine 7.2 mg/kg against disseminated cryptococcosis with the H99 strain, but only at a low infecting inoculum. In contrast, both fluconazole and amphotericin B significantly improved survival in mice with cryptococcal meningoencephalitis and disseminated cryptococcosis due to USC1597. Amphotericin B also improved survival against both cryptococcal infections caused by H99. Combination therapy with miltefosine demonstrated neither synergy nor antagonism in both models. These results demonstrate limited efficacy of miltefosine and suggest caution with the potential use of this agent for the treatment of C. neoformans infections.
FOOTNOTES
Corresponding Author: Nathan P. Wiederhold, Pharm.D., UTHSCSA, PERC MSC 6220, 7703 Floyd Curl Drive, San Antonio, TX 78229, Phone: 210-567-8340, Fax: 210-567-8328, Email: wiederholdn@uthscsa.edu
Copyright ? 2012, American Society for Microbiology. All Rights Reserved.
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