Inhalation of fresh water containing the free-living ameba Naegleria fowleri may lead to a potentially fatal infection known as primary amebic meningoencephalitis. Amphotericin B is the only agent with established clinical efficacy in the treatment of primary amebic meningoencephalitis in humans, but therapy with this drug is often associated with adverse effects on the kidneys and other organs, and not all persons treated with amphotericin B have survived. We investigated the in vitro activity and in vivo efficacy of newer therapeutic agents in an attempt to identify other useful agents for treating primary amebic meningoencephalitis. Azithromycin has shown in vitro activity against Acanthamoeba spp. and in vivo activity against experimental toxoplasmosis. In our study, the MIC of azithromycin against N. fowleri was 13.4 M (10 g/ml), which was 123 times greater than the MIC of amphotericin B, which was 0.108 M (0.1 g/ml). Azithromycin protected 100% of mice infected with N. fowleri at a dose of 75 mg/kg/day for 5 days, whereas amphotericin B protected only 50% of mice at a dose of 7.5 mg/kg/day for 5 days, and all control mice died during the 28-day observation period. We conclude that azithromycin has both in vitro and in vivo activity versus N. fowleri and may be a useful addition to therapy for primary amebic meningoencephalitis.Primary amebic meningoencephalitis is a rapidly fatal infection caused by the free-living ameba Naegleria fowleri. Victims are usually healthy, young individuals with a recent history of swimming or other water-related activities. N. fowleri gains entry to the nasal cavity during inhalation or aspiration of contaminated water. The ameba then migrates along the olfactory nerves, crosses the cribriform plate, and gains access to the central nervous system. Within the brain, N. fowleri causes extensive inflammation, hemorrhage, and necrosis, leading to death in 3 to 7 days (12).Mortality among patients with primary amebic meningoencephalitis is greater than 95% (4). This grave prognosis is due to the rapid progression of the disease, the often delayed diagnosis, and the lack of effective therapeutic agents. Since primary amebic meningoencephalitis was identified, a wide range of therapeutic agents against N. fowleri have been evaluated, including many antifungal, antiprotozoal, antibacterial, and antipsychotic agents. Most of these drugs were determined to have little or no efficacy against N. fowleri, either in vitro or in vivo (5)(6)(7)(8)22).Of the drugs that have been evaluated against N. fowleri, amphotericin B, an antifungal drug, is the only agent with established clinical efficacy. Studies have demonstrated the in vitro and in vivo activity of amphotericin B against various strains of N. fowleri (5-8, 13, 17, 19, 20, 21), and at least seven patients with primary amebic meningoencephalitis have been successfully treated with amphotericin B alone or in combination with other drugs (1,2,14,16,19,25).Although amphotericin B remains the first choice for treatment of primary amebic me...

One new and one known isoflavan, 3 S(+)-7-methoxymanuifolin K (1) and manuifolin K (2), respectively, were isolated from methanolic extracts of Dalea aurea (Fabaceae). Isoflavans 1 and 2 exhibited significant in vitro activity against the ameba Naegleria fowleri, an organism responsible for an infrequent but rapidly fatal form of primary amebic meningoencephalitis (PAM). At concentrations of 30 microM, both 1 and 2 caused growth inhibition of N. fowleri at a level comparable to amphotericin B (at 0.1 microM), the currently preferred treatment for this disease. Over a seven-day growth period, 1 and 2 (30 microM) exhibited superior growth inhibition of N. fowleri than amphotericin B after day 4. Isoflavan 2 was evaluated in a mouse model of PAM at a dose of 25 mg/kg/day for five days. While amphotericin B (2.5 mg/kg/day) offered 12.5 % protection of the mice, compound 2 did not protect the mice from PAM infection compared to controls.

Inhalation of water contaminated with Naegleria fowleri may lead to a potentially fatal infection of the central nervous system known as primary amebic meningoencephalitis (PAM). Amphotericin B (AMB), an antifungal drug, is the only agent with established clinical efficacy in the treatment of PAM, though therapy with this drug is not always effective and has been associated with adverse effects on the kidneys and other organs. We investigated the activity of various therapeutic agents against N. fowleri in an attempt to identify other useful agents for treating PAM. Several of these agents exhibited in vitro activity against the Lee (M67) strain of N. fowleri. The minimum inhibitory concentrations of these agents were 0.1 microg/ml (ketoconazole), 1 microg/ml (liposomal AMB), and 10 microg/ml (minocycline, quinupristin-dalfopristin, and trifluoperazine). Other agents had a minimum inhibitory concentration > 10 microg/ml (linezolid) or > 100 microg/ml (rifampin). In a mouse model of PAM, none of the untreated control mice survived, whereas the survival of treated animals was 50% (quinupristin-dalfopristin), 30% (ketoconazole and liposomal AMB), 20% (trifluoperazine), and 10% (linezolid and minocycline). Further studies are needed to ascertain whether these agents have synergistic activity with AMB in vitro and in vivo.