Clinicians: For 24/7 diagnostic assistance, specimen collection guidance, shipping instructions, and treatment recommendations, please contact the CDC Emergency Operations Center at 770-488-7100.
Clinicians: CDC now has an investigational drug called miltefosine available for treatment of free-living ameba (FLA) infections caused by Naegleria fowleri, Balamuthia mandrillaris, and Acanthamoeba species. If you have a patient with suspected FLA infection, please contact the CDC Emergency Operations Center at 770-488-7100 to consult with a CDC expert regarding the use of this drug.
Although most cases of primary amebic meningoencephalitis (PAM) caused by Naegleria fowleri infection have been fatal 1, there have been four well-documented survivors (one from the U.S. in 1978 2, 3 , one from Mexico in 2003 4, and two from the U.S. in 2013 5, 6) who received the following treatment courses:
|U.S. Survivor 2, 3 (1978)||Mexico Survivor 4 (2003)||U.S. Female Survivor 5 (2013)||U.S. Male Survivor (2013) 6|
|Amphotericin B (IV and intrathecal)||Amphotericin B (IV)||Amphotericin B (IV and intrathecal)||Amphotericin B (IV and intrathecal)|
|Rifampin (oral)||Rifampin (oral)||Rifampin (IV/oral)||Rifampin (oral)|
|Miconazole (IV and intrathecal) – no longer available in US||Fluconazole (IV and oral)||Fluconazole (IV/oral)||Fluconazole (IV)|
|Dexamethasone||Dexamethasone (IV)||Dexamethasone (IV)||Dexamethasone (IV)|
|Sulfisoxazole (IV) – discontinued after Naegleria diagnosed||Ceftriaxone (IV)||Azithromycin (IV/oral)||Azithromycin (oral)|
|Phenytoin||Miltefosine (oral)||Miltefosine (oral)|
Based on the treatment regimens used in the survivors, including the 2013 case-patients, the following combination of drugs is recommended for treatment of PAM:
|Amphotericin B *2||1.5 mg/kg/day in 2 divided doses||IV||1.5 mg/kg/day||3 days|
|1 mg/kg/day once daily||IV||11 days||14-day course|
|Amphotericin B * 2||1.5 mg once daily||Intrathecal||1.5 mg/day||2 days|
|then||1 mg/day every other day||Intrathecal||8 days||10-day course|
|Azithromycin 8, 11||10 mg/kg/day once daily||IV/PO||500 mg/day||28 days|
|Fluconazole 4||10 mg/kg/day once daily||IV/PO||600 mg/day||28 days|
|Rifampin 2||10 mg/kg/day once daily||IV/PO||600 mg/day||28 days|
|Miltefosine **||Weight<45 kg 50 mg BID
Weight>45kg 50 mg TID
|PO||2.5 mg/kg/day||28 days||50 mg tablets|
|Dexamethasone 4, 18||0.6 mg/kg/day in 4 divided doses||IV||0.6 mg/kg/day||4 days|
* Conventional amphotericin (AMB) is preferred. When AMB was compared with liposomal AMB against Naegleria fowleri, the minimum inhibitory concentration (MIC) for AMB was 0.1 µg/mL, while that of liposomal AMB was 10x higher at 1 µg/ml. Liposomal AMB was found to be less effective in the mouse model and in in vitro testing than the more toxic form of AMB 7,8. AMB methyl ester was also found to be less effective in the mouse model 9,10. Because of the extremely poor prognosis of Naegleria fowleri infection, it’s worth considering aggressive treatment.
** The investigational drug, miltefosine 12, a breast cancer and anti-leishmania drug, has shown some promise against the free-living amebae in combination with some of these other drugs. Miltefosine has shown in vitro and mouse model amebicidal activity against Balamuthia, Naegleria fowleri, and Acanthamoeba 13, 14, 15 and has been used to successfully treat patients with Balamuthia infection 16 and disseminated Acanthamoeba infection 17. The standard miltefosine dosing in adults is as follows:
- Up to 45 kg body weight: 100 mg daily (i.e., one 50 mg cap po BID, given with food if possible to reduce gastrointestinal side effects)
- 45 kg body weight and higher: 150 mg daily (i.e., one 50 mg cap po TID, given with food if possible to reduce gastrointestinal side effects )
These standard doses are the maximal tolerated with respect to gastrointestinal symptoms. A higher dose would lead to increased nausea, vomiting, or diarrhea. Miltefosine is mildly nephrotoxic and the dosing might need to be adjusted for patients with impaired kidney function. However, because few data are available about the effective dose for amebic infection, the risk for nephrotoxicity should be balanced with the risk for mortality from PAM. CDC now has a supply of miltefosine for treatment of Naegleria fowleri infection. If you have a patient with suspected Naegleria or other free-living ameba infection, please contact the CDC Emergency Operations Center at 770-488-7100 to consult with a CDC expert regarding the use of this drug.
- Yoder JS, Eddy BA, Visvesvara GS, Capewell L, Beach MJ. The epidemiology of primary amoebic meningoencephalitis in the USA, 1962-2008. Epidemiol Infect. 2010;138:968-75.
- Seidel J, Harmatz P, Visvesvara GS, Cohen A, Edwards J, Turner J. Successful treatment of primary amebic meningoencephalitis. New Engl J Med 1982;306:346-8.
- Visvesvara GS, Moura H, Schuster FL. Pathogenic and opportunistic free-living amoebae: Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri, and Sappinia diploidea. FEMS Immunol Med Microbiol. 2007;50:1-26.
- Vargas-Zepeda J, Gomez-Alcala AV, Vasquez-Morales JA, Licea-Amaya L, De Jonckheere JF, Lores-Villa F. Successful treatment of Naegleria PAM using IV amphotericin B, fluconazole, and rifampin. Arch Med Res. 2005;36:83-6.
- Linam WM, Ahmed M, Cope JR, Chu C, Visvesvara GS, da Silva AJ, Qvarnstrom Y, Green J. Successful treatment of an adolescent with Naegleria fowleri primary amebic meningoencephalitis. Pediatrics. 2015; 135: e744–8.
- Cope JR, Conrad DA, Cohen N, Cotilla M, DaSilva A, Jackson J, Visvesvara GS. Use of the novel therapeutic agent miltefosine for the treatment of primary amebic meningoencephalitis: report of 1 fatal and 1 surviving case. Clin Infect Dis 2016;62:774-6.
- Goswick SM, Brenner GM. Activities of therapeutic agents against Naegleria fowleri in vitro and in a mouse model of primary amebic meningoencephalitis. J Parasitol. 2003;89:837-42.
- Goswick SM, Brenner GM. Activities of azithromycin and amphotericin B against Naegleria fowleri in vitro and in a mouse model of primary amebic meningoencephalitis. [PDF - 5 pages] Antimicrob Agents Chemother. 2003;47:524-8.
- Ferrante A. Comparative sensitivity of Naegleria fowleri to amphotericin B and amphotericin B methyl ester. Trans R Soc Trop Med Hyg. 1982;76:476-8.
- Lee KK, Karr SL Jr, Wong MM, Hoeprich PD. In vitro susceptibilities of Naegleria fowleri strain HB-1 to selected antimicrobial agents, singly and in combination. Antimicrob Agents Chemother. 1979;16:217-20.
- Soltow SM, Brenner GM. Synergistic activities of azithromycin and amphotericin B against Naegleria fowleri in vitro and in a mouse model of primary amebic meningoencephalitis. [PDF - 5 pages] Antimicrob Agents Chemother. 2007;51:23–7.
- Kaminsky R. Miltefosine Zentaris. Curr Opin Investig Drugs. 2002;3:550-4.
- Schuster FL, Guglielmo BJ, Visvesvara GS. In-vitro activity of miltefosine and voriconazole on clinical isolates of free-living amebas: Balamuthia mandrillaris, Acanthamoeba spp., and Naegleria fowleri. J Eukaryot Microbiol. 2006;53:121-6.
- Kim JH, Jung SY, Lee YJ, Song KJ, Kwon D, Kim K, Park S, Im KI, Shin HJ. Effect of therapeutic chemical agents in vitro and on experimental meningoencephalitis due to Naegleria fowleri. [PDF - 7 pages] Antimicrob Agents Chemother. 2008;52:4010-16.
- Walochnik J, Obwaller A, Gruber F, Mildner M, Tschachler E, Suchomel M, Duchene M, Auer H. Anti-Acanthamoeba efficacy and toxicity of miltefosine in an organotypic skin equivalent. J Antimicrob Chemother. 2009;64:539-45.
- Martínez DY, Seas C, Bravo F, Legua P, Ramos C, Cabello AM, Gotuzzo E. Successful treatment of Balamuthia mandrillaris amoebic infection with extensive neurological and cutaneous involvement. Clin Infect Dis. 2010;51:e7-11.
- Aichelburg AC, Walochnik J, Assadian O, Prosch H, Steuer A, Perneczky G, Visvesvara GS, Aspöck H, Vetter N. Successful treatment of disseminated Acanthamoeba sp. infection with miltefosine. [PDF - 4 pages] Emerg Infect Dis. 2008;14:1743-6.
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