In‐Vitro Activity of Miltefosine and Voriconazole on Clinical Isolates of Free‐Living Amebas: Balamuthia mandrillaris, Acanthamoeba spp., and Naegleria fowleri

Abstract

The anticancer agent miltefosine and the antifungal drug voriconazole were tested in vitro against Balamuthia mandrillaris, Acanthamoeba spp., and Naegleria fowleri. All three amebas are etiologic agents of chronic (Balamuthia, Acanthamoeba) or fulminant (Naegleria) encephalitides in humans and animals and, in the case of Acanthamoeba, amebic keratitis. Balamuthia exposed to <40 microm concentrations of miltefosine survived, while concentrations of >or=40 microM were generally amebacidal, with variation in sensitivity between strains. At amebastatic drug concentrations, recovery from drug effects could take as long as 2 weeks. Acanthamoeba spp. recovered from exposure to 40 microM, but not 80 microM miltefosin. Attempts to define more narrowly the minimal inhibitory (MIC) and minimal amebacidal concentrations (MAC) for Balamuthia and Acanthamoeba were difficult due to persistence of non-proliferating trophic amebas in the medium. For N. fowleri, 40 and 55 microM were the MIC and MAC, respectively, with no trophic amebas seen at the MAC. Voriconazole had little or no inhibitory effect on Balamuthia at concentrations up to 40 microg/ml, but had a strong inhibitory effect upon Acanthamoeba spp. and N. fowleri at all drug concentrations through 40 microg/ml. Following transfer to drug-free medium, Acanthamoeba polyphaga recovered within a period of 2 weeks; N. fowleri amebas recovered from exposure to 1 microg/ml, but not from higher concentrations. All testing was done on trophic amebas; drug sensitivities of cysts were not examined. Miltefosine and voriconazole are potentially useful drugs for treatment of free-living amebic infections, though sensitivities differ between genera, species, and strains.

Therapeutic effect of rokitamycin in vitro and on experimental meningoencephalitis due to Naegleria fowleri

“…Azithromycin has been described for the effective treatment of experimental PAME in mice [9]. In recent years, miltefosine, which was used as an anticancer drug, and voriconazole, which was used in systemic fungal infections, were found to be effective in in vitro studies [10].…”

Biology and pathogenesis of Naegleria fowleri

“…Control and Prevention (CDC) recommends that patients suspected of PAM should be given the following combination of drugs: deoxycholate amphotericin B intravenously (IV) and intrathecally (IT), an azole drug such as fluconazole IV or orally (PO), azithromycin IV or PO, rifampin IV or PO, miltefosine PO, and dexamethasone IV ( indicating that the combined use of these two drugs may result in successful prognosis (39,46,47).…”

“…Miltefosine is an anticancer agent, that showed potent activity against N. fowleri in vitro and in vivo effects (46,48,49). Notably, miltefosine can cross the blood-brain barrier and concentrate in brain tissue, thus making this a useful drug against PAM.…”

Free living amoebae and human disease

“…These cases have received varied combination therapy regimens, with agents including pentamidine, flucytosine, fluconazole, macrolides, sulfadiazine, miltefosine, thioridazine, amphotericin B, albendazole and trimethoprim-sulfamethoxazole. Miltefosine, in particular, has demonstrated amoebicidal activity in vitro 37 and its inclusion in combination regimens may offer a survival advantage 35 .…”