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Parasites

Treatment

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. More detailed guidance is under Information for Public Health & Medical Professionals.

Clinicians: CDC no longer provides miltefosine for treatment of free-living ameba infections. Miltefosine is now commercially available. Please visit impavido.com for more information on obtaining miltefosine in the United States. If you have a patient with suspected 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.

Although most cases of primary amebic meningoencephalitis (PAM) caused by Naegleria fowleri infection have been fatal 1, there have been five well-documented survivors (one from the U.S. in 1978 2,3 , one from Mexico in 2003 4, two from the U.S. in 2013 5,6, and one from the U.S. in 2016) who received the following treatment courses:

Survivor Medications

U.S. Survivor 1, 2 (1978) Mexico Survivor 3 (2003) U.S. Female Survivor 4 (2013) U.S. Male Survivor (2013) 5
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)

*The 2016 U.S. survivor received the same treatment protocol as the 2013 U.S. female survivor.

References
  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.

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:

Recommended Treatment for Primary Amebic Meningoencephalitis Caused by Naegleria fowleri

Drug Dose Route Maximum Dose Duration Comments
Amphotericin B *1 1.5 mg/kg/day in 2 divided doses IV 1.5 mg/kg/day 3 days  

then

 1 mg/kg/day once daily IV   11 days 14-day course
Amphotericin B *1 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 2,3 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 1 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 4,5 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 6,2. AMB methyl ester was also found to be less effective in the mouse model 7,8. Because of the extremely poor prognosis of Naegleria fowleri infection, it’s worth considering aggressive treatment.

** Miltefosine 9, 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 10-12 and has been used to successfully treat patients with Balamuthia infection 13 and disseminated Acanthamoeba infection 14. The standard miltefosine dosing in adults is as follows:

Miltefosine (oral)

  • 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. 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.

References
  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. van de Beek D, de Gans J, McIntyre P, Prasad K. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev. 2007(1):CD004405
  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.
  7. 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.
  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.
  9. Kaminsky R. Miltefosine Zentaris. Curr Opin Investig Drugs. 2002;3(4):550-4.
  10. 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(2):121-6.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
References
  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.

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