title: Limited activity of miltefosine in murine models of cryptococcal meningoencephalitis and disseminated cryptococcosis.
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 to 45 mg/kg of body weight orally once daily) began at either 1 h or 1 day postinoculation. 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 toward improved survival with miltefosine at 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.
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA. wiederholdn@uthscsa.edu
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Wiederhold
authors.forename: Laura K
authors.initials: LK
authors.lastname: Najvar
authors.forename: Rosie
authors.initials: R
authors.lastname: Bocanegra
authors.forename: William R
authors.initials: WR
authors.lastname: Kirkpatrick
authors.forename: Tania C
authors.initials: TC
authors.lastname: Sorrell
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Patterson
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage; D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D003453:Cryptococcosis / Q000188:drug therapy* / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000187:drug effects* / Q000302:isolation & purification; D003840:Deoxycholic Acid / Q000008:administration & dosage; D004338:Drug Combinations; D015725:Fluconazole / Q000008:administration & dosage; D016919:Meningitis, Cryptococcal / Q000188:drug therapy* / Q000382:microbiology; D008590:Meningoencephalitis / Q000188:drug therapy* / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013534:Survival
chemical_list: D000935:Antifungal Agents; D004338:Drug Combinations; D003840:Deoxycholic Acid; D010767:Phosphorylcholine; C039128:miltefosine; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination; D015725:Fluconazole