Naegleria fowleri

Author: Jennifer R. Cope, MD, MPH

Author: First and Second Edition, 1999 and 2002: Stan Deresinski, M.D.

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History

The free-living amoebae that are pathogenic for man are comprised of three genera:Acanthamoeba, Balamuthia, and Naegleria, all belonging to the superclass, Rhizopodea. Pathogenic species of all three genera are preferentially neurotropic in the human host.Naegleria fowlericauses primary amebic meningoencephalitis (PAM).

Parasitology

Life Cycle

The only species ofNaegleriaknown to be capable of causing human disease is Naegleria fowleri. The organism exists in the environment as an amoeboid or amoeboflagellate trophozoite that feeds upon bacteria and other organic matter but, under unfavorable conditions, encysts. In the human host, it exists only as a motile trophozoite and the diagnosis ofprimary amebic meningoencephalitiscan be made upon the visualization of this form of the organism in either cerebrospinal fluid or brain tissue.

Epidemiology

Free-living amoebae have worldwide distribution and may be found in water and soil. Although human infection is rare, cases have been reported from North, Central, and South America, as well as Europe, Asia, Africa, and Australia.Naegleria fowleriis thermophilic and grows well even at temperatures of up to 115°F. In temperate climates, most cases occur in the summer months, while in tropical and semitropical areas, seasonality may be absent, occurring in individuals who have been exposed to warm fresh water, as well as hot springs. In colder climates, these amoebae will encyst and remain dormant in the sediments of fresh water lakes, ponds, and rivers. Recently, the epidemiology ofNaegleria fowlerihas changed. In the United States, most cases occur in southern-tier states, but in 2010, the first case was reported from the northern state of Minnesota, with cases subsequently reported again from Minnesota, as well as Indiana, and Kansas, suggesting that the geographic range of this thermophilic organism may be expanding (8). Additionally, while most cases are associated with recreational water use, recent infections have been reported in patients exposed to nonsterile tap water used for nasal irrigation (e.g., neti pot use and ritual ablution) (3,19).

Clinical Manifestations

Patients with primary amebic meningoencephalitis present after an incubation period of 3 to 5 days, with fulminant, usually fatal meningitis which clinically resembles acute bacterial infection. Headache is severe and rapid progression to coma is common. Survival, which has been uncommon, is likely dependent upon immediate diagnosis and institution of therapy, discussed below.

Laboratory Diagnosis

The cerebrospinal fluid (CSF) has high concentrations of neutrophils and the glucose concentration is generally low and the protein elevated in patients with meningitis. Increased numbers of erythrocytes may be present. CSF pressure is commonly elevated. The diagnosis may be made by visualization in freshly obtained unstained CSF of motile amoebae with rapid formation of blunt pseudopodia and monopodial locomotion. Confirmation of the diagnosis can be made by detection of Naegleria fowleri antigen in brain tissue using immunohistochemistry or indirect immunofluorescence techniques or detection of Naegleria fowleri DNA using a real-time PCR assay on CSF or brain tissue.

Pathogenesis

Infection occurs when fresh water containing the ameba enters the nose allowing the ameba to gain access to the olfactory neuroepithelium. Trophozoites are the invasive form of the organism. The non-flagellate trophozoites are believed to be actively phagocytosed by sustenacular cells of the olfactory neuroepithelium and then migrate along the olfactory nerves into the subarachnoid space, subsequently invading tissue of the central nervous system, causing hemorrhagic necrosis and edema (11).

SUSCEPTIBILITY IN VITRO AND IN VIVO

There is no standardized method ofin vitrosusceptibility testing. In vitro susceptibility results, performed and expressed in a variety of ways, have been reported for a limited number of strains. The drug which is most consistently reported as inhibitingNaegleriaat clinically relevant concentrations is amphotericin B. However, newer lipid-associated formulations of amphotericin B (amphotericin B lipid complex, liposomal amphotericin B) have higher minimum inhibitory concentrations (MICs) (6,7). Azole agents, including ketoconazole, fluconazole, itraconazole, and voriconazole, have also shown effective inhibitory activity against N. fowleri (5,12,17). The macrolide antibiotics azithromycin and clarithromycin have demonstratedin vitroactivity against N. fowleri, with azithromycin showing synergism with amphotericin B (13,15). Additionally, miltefosine, an antiparasitic agent approved for the treatment of leishmaniasis, has shown amebacidal activity against N. fowleri (12).

Murine models of N, fowleriinfection support in vitro findings. Amphotericin B, azithromycin, and miltefosine all have been shown to improve mouse survival relative to untreated controls (9). Amphotericin B and rifampin appeared to be synergistic (16).

ANTIPARASITIC THERAPY

Since there are no randomized clinical trials in humans, published case reports provide us with the most useful information on therapy for this infection. Treatment recommendations rely on a few well-documented primary amebic meningoencephalitis survivors (1,2,10,14,18). Based on these survivors, the following treatment is recommended forprimary amebic meningoencephalitis patients: 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, and miltefosine PO (Table 1). All of the well-documented survivors received deoxycholate amphotericin B intravenously, generally in doses of 1.0 mg/kg/d to 1.5 mg/kg/d, for approximately two weeks. In some of the survivors, amphotericin B was also administered intrathecally at a dose of 1.5 mg per day for 2 days following by 1.0 mg per day for 8 days (10,14). The deoxycholate formulation is preferred because of thein vitrodata showing lower MICs when compared with lipid formulations. However, if only a lipid formulation is available at the time aprimary amebic meningoencephalitis diagnosis is suspected, then a lipid formulation can be used to facilitate prompt treatment of the patient. Miltefosine has limited availability in the United States. The U.S. Centers for Disease Control and Prevention maintains a small supply of miltefosine under an expanded access Investigational New Drug (IND) protocol for use in treating free-living ameba infections. Clinicians who are treating a patient with suspectedprimary amebic meningoencephalitis should contact CDC (770-488-7100) to speak with a CDC expert regarding the use of miltefosine.

The appropriate duration of therapy is uncertain, but should probably be at least 10–14 days of amphotericin B, with the actual duration depending upon rapidity of clinical and microbiological response in the individual patient. Azithromycin, fluconazole, rifampin, and miltefosine were given for 28 days in the recent survivor cases (2,10).

ADJUNCTIVE THERAPY

Adjunctive therapies for primary amebic meningoencephalitis patients should be focused on aggressively managing the cerebral edema and elevated intracranial pressure that ultimately leads to brain herniation and death in these patients. Most of the well-documented survivors received dexamethasone in order to control the inflammatory process. The most recent well-documented survivor who recovered with no apparent neurologic sequelae was managed aggressively for elevated intracranial pressure. Management of this individual included drainage of CSF via an external ventricular drain, hyperosmolar therapy with mannitol and 3% saline, moderate hyperventilation (goal P_aCO2: 30–35 mm Hg), and induced hypothermia (32–34°Celsius) (10).

ENDPOINTS OF MONITORING THERAPY

Cerebrospinal fluid parameters, as well as clinical status are monitored to assess the duration of therapy.

VACCINES

There are no vaccines for Naegleria species.

PREVENTION

Since the cystic and trophic forms ofNaegleria fowleri are susceptible to chlorine, adequate chlorination and maintenance of swimming pools and water distribution systems can prevent primary amebic meningoencephalitis. Personal actions to reduce the risk ofprimary amebic meningoencephalitis should focus on limiting the amount of water going up the nose when participating in recreational activities in warm freshwater and lowering the chances that N. fowleri may be in the water when using tap water for nasal rinsing. Tap water that is used for nasal rinsing should be boiled and left to cool, filtered using a filter labeled as "absolute pore size of 1 micron or smaller", disinfected using chlorine bleach, or bought as distilled or sterile water.

REFERENCES

1. Anderson K, Jamieson A. Primary amoebic meningoencephalitis. Lancet 1972;1:902-903. [PubMed]

2. Capewell LG, Harris AM, Yoder JS, Cope JR, Eddy BA, Roy SL, Visvesvara GS, Fox LM, Beach MJ. Diagnosis, clinical course, and treatment of primary amoebic meningoencephalitis in the United States, 1937-2013. J Pediatr Infect Dis Soc. 2014; Epub: 1–8.

3. Centers for Disease Control and Prevention. Primary amebic meningoencephalitis associated with ritual nasal rinsing — St. Thomas, U.S. Virgin Islands, 2012. MMWR Morb Mortal Wkly Rep. 2013;62: 903. [PubMed]

4. Duma RJ. In vitro susceptibility of pathogenic Naegleria gruberi to amphotericin B. Antimicrob Agents Chemother 1970;10:109-11. [PubMed]

5. Duma RJ, Finley R. In vitro susceptibility of pathogenic Naegleria and Acanthamoeba species to a variety of therapeutic agents. Antimicrob Agents Chemother 1976;10:370-6. [PubMed]

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. [PubMed]

7. Goswick SM, Brenner GM. Activities of azithromycin and amphotericin B against Naegleria fowleri in vitro and in a mouse model of primary amebic meningoencephalitis. Antimicrob Agents Chemother 2003;47:524-8. [PubMed]

8.Kemble SK, Lynfield R, DeVries AS, Drehner DM, Pomputius WF 3rd, Beach MJ, Visvesvara GS, da Silva AJ, Hill VR, Yoder JS, Xiao L, Smith KE, Danila R. FatalNaegleria fowleriinfection acquired in Minnesota: possible expanded range of a deadly thermophilic organism.Clin Infect Dis. 2012; 54: 805-9. [PubMed]

9. 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. Antimicrob Agents Chemother 2008;52:4010-6. [PubMed]

10. 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. [PubMed]

11. Martinez J, Duma RJ, Nelson EC, Moretta FL. Experimental Naegleria meningoencephalitis in mice. Lab Invest 1973;29:121-133. [PubMed]

12. 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. [PubMed]

13. Schuster FL DT, Visvesvara GS. Activity of selected antimicrobials against clinical isolates of pathogenic free-living amebas. Paris, France: John Libbey Eurotext, 2001.

14. Seidel JS, Harmatz P, Visvesvara GS, Cohen A, Edwards J, Turner J. Successful treatment of primary amebic meningoencephalitis. New Engl J Med 1982;306:346-348. [PubMed]

15.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. Antimicrob Agents Chemother 2007;51:23-7. [PubMed]

16. Thong YH, Rowan-Kelly B, Ferrante A. Treatment of experimental Naegleria meningoencephalitis with a combination of amphotericin B and rifamycin. Scand J Infect Dis 1979; 11: 151-153. [PubMed]

17. Tiewcharoen S, Junnu V, Chinabut P.In vitroeffect of antifungal drugs on pathogenic Naegleria spp. Southeast Asian J Trop Med Public Health 2002;33:38-41. [PubMed]

18.Vargas-Zepeda J, Gomez-Alcala AV, Vasquez-Morales JA, Licea-Amaya L, De Jonckheere JF, Lares-Villa F. Successful treatment of Naegleria fowleri meningoencephalitis by using intravenous amphotericin B, fluconazole and rifampicin. Arch Med Res 2005;36:83-6. [PubMed]

19. Yoder JS, Straif-Bourgeois S, Roy SL, Moore TA, Visvesvara GS, Ratard RC, Hill V, Wilson JD, Linscott AJ, Crager R, Kozak NA, Sriram R, Narayanan J, Mull B, Kahler AM, Schneeberger C, da Silva AJ, Beach MJ.Primary amebic meningoencephalitis deaths associated with sinus irrigation using contaminated tap water.Clin Infect Dis 2012;55:e79-85.[PubMed]

Tables

Table 1. Recommended Treatment for Primary Amebic Meningoencephalitis Caused byNaegleria fowleri

Drug	Dose	Route	Maximum Dose	Duration	Comments
Amphotericin B	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	1.5 mg once daily	Intrathecal	1.5 mg/day	2 days
then	1 mg/day every other day	Intrathecal		8 days	10-day course
Azithromycin	10 mg/kg/day once daily	IV/PO	500 mg/day	28 days
Fluconazole	10 mg/kg/day once daily	IV/PO	600 mg/day	28 days
Rifampin	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	0.6 mg/kg/day in 4 divided doses	IV	0.6 mg/kg/day	4 days