title: In vitro activity of miltefosine as a single agent and in combination with voriconazole or posaconazole against uncommon filamentous fungal pathogens.
abstract: OBJECTIVE
  Antifungal treatment of uncommon filamentous fungal infections is problematic. This study determined the in vitro susceptibility of miltefosine, as a single agent and in combination with posaconazole or voriconazole, against these pathogens.
  
  
  METHODS
  Susceptibility to miltefosine of 34 uncommon filamentous fungi was tested using CLSI broth microdilution M38-A2 methodology. Twenty isolates were studied for potential synergy using miltefosine/posaconazole and miltefosine/voriconazole combinations and the chequerboard microdilution assay.
  
  
  RESULTS
  MICs of miltefosine were high (in general, >8 mg/L) for most isolates compared with amphotericin B, echinocandins and the azoles. Miltefosine had greatest activity against Scedosporium spp., Lichtheimia corymbifera and Rhizomucor sp. (MICs ≤ 4 mg/L). Miltefosine in combination either with posaconazole or voriconazole demonstrated synergy [fractional inhibitory concentration index (FICI) ≤ 0.5] in 12 instances (11 isolates): miltefosine/posaconazole combinations were synergistic against 3 of 4 Fusarium oxysporum strains (FICI range 0.37-0.5) and 5 of 10 mucormycete strains (FICI range 0.06-0.5). The combination of voriconazole with miltefosine showed synergy against one Scedosporium prolificans isolate and three mucormycetes-a single strain each of L. corymbifera, Rhizopus oryzae and Rhizomucor sp. No antagonism was observed.
  
  
  CONCLUSIONS
  Miltefosine demonstrated synergy in 8/20 (40%) and 4/20 (20%) instances when combined with posaconazole and voriconazole, respectively. Synergy was most often observed against F. oxysporum and the mucormycetes. Study of miltefosine/azole combinations as a novel antifungal approach is indicated.
authors.affiliation: Centre for Infectious Diseases and Microbiology, Westmead Millennium Institute, Sydney, Australia.
authors.forename: Chayanika
authors.initials: C
authors.lastname: Biswas
authors.forename: Tania C
authors.initials: TC
authors.lastname: Sorrell
authors.forename: Julianne T
authors.initials: JT
authors.lastname: Djordjevic
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zuo
authors.forename: Katrina A
authors.initials: KA
authors.lastname: Jolliffe
authors.forename: Sharon C-A
authors.initials: SC
authors.lastname: Chen
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D004357:Drug Synergism; D005658:Fungi / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D008826:Microbial Sensitivity Tests; D009181:Mycoses / Q000382:microbiology; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D010767:Phosphorylcholine; C039128:miltefosine; C101425:posaconazole; D065819:Voriconazole
keywords: mucormycetes; susceptibility; synergy