In vitro activity of miltefosine as a single agent and in combination with voriconazole or posaconazole against uncommon filamentous fungal pathogens.

ABSTRACT

OBJECTIVES: 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.