Standard treatment emerges for N. fowleri

Issue: April 2017

Naegleria fowleri, a free-living amoeba, lives in the warm freshwaters of the world, including in the United States. Infections by brain-eating amoeba have been reported to occur in lakes, ponds, hot springs, nonchlorinated swimming pools, and tap water. N. fowleri infections have a high mortality rate. Although still rare, cases of primary amebic meningoencephalitis, or PAM, caused by N. fowleri have been reported in increasing numbers, although the number of infections is thought to be stable. As understanding of N. fowleri infections increases, a successful treatment regimen has emerged, relying on multiple medications and early administration.

N. fowleri lives in optimal water temperatures of 46oC (115oF). The amoeba can survive for extended periods of time in cold water above freezing and for hours at 50-65oC (122-149oF). Once introduced through the nasal mucosa, N. fowleri moves across the pores of the cribriform plate into the olfactory bulb. Immune cells move into the infection site, causing damage to the blood-brain barrier and allowing the amoeba to penetrate the brain. After disseminating to other tissues in the brain, an acute inflammatory reaction is mounted by the host. Mediated by interleukin-1 (IL-1), beta tumor necrosis factor (beta-TNF), histamine, prostacyclin (PGI2) and other cytokines, the inflammatory reaction causes tissue damage, necrosis and increased permeability of the surrounding vasculature.

Due to the initial site of infection, symptoms early on can be consistent with respiratory infection and may include changes in senses of smell and taste. Changes in personality and possible seizures are observed as N. fowleri moves through the frontal lobe. Symptoms then resemble classic meningitis presentation: headache, confusion, stiff neck, nausea, vomiting and fever. As the infection continues, toxins and proteases are released by the amoeba, further damaging the tissues. Edema, increased intracranial pressures and herniation, in most cases, result in death for the patient. Diagnosis is made by identifying N. fowleri trophozoites and motile amoeba in the cerebral spinal fluid (CSF) or through Giemsa-Wright staining. Specialized laboratory tests can also identify nucleic acids with PCR or antigens in the CSF or with tissue specimens. N. fowleri can also be cultured in a bacteria-covered growth plate incubated at 42oC (108oF). Initial identification may be made by the amoeba’s tracks as it moves across the plate to consume the bacteria, followed by further testing with stains, PCR or antigen. Although other amoebas may cause tracks, it is reasonable to begin treatment without speciation due to the virulence of N. fowleri.

To our knowledge, there have been only four survivors of PAM due to N. fowleri in North America — three in the U.S. and one in Mexico. In each case, quick identification and treatment contributed to survival. In each of the recent cases, patients received both IV and intrathecal amphotericin B, oral rifampin, IV fluconazole, IV dexamethasone, azithromycin and oral miltefosine (Table). Aggressive management of elevated intracranial pressures also contributed to patients’ survival. Although amphotericin B remains the cornerstone treatment of N. fowleri infections, new therapies are being investigated as awareness and understanding of these infections improves. Voriconazole has been shown to be effective in vitro. Chlorpromazine, an antiemetic agent, has shown efficacy in vitro and in animal studies, in combination with other medications.

Amphotericin B

Amphotericin B is an antifungal agent that binds to sterols, disrupting cell membranes. Amphotericin B has well-documented efficacy against N. fowleri, possibly working synergistically with azithromycin to kill the amoeba. Severe toxicity can occur with amphotericin B, including infusion reaction, nephrotoxicity, nausea, vomiting, changes in blood pressure, hypokalemia and hypomagnesemia. Sodium loading and hydrating patients have been shown to decrease nephrotoxicity associated with amphotericin B. This can be accomplished by giving normal saline boluses before and after the dose. Clinicians should monitor electrolytes, renal function and phosphates throughout treatment. Conventional amphotericin B is preferred over liposomal amphotericin B due to higher minimum inhibitory concentrations — 0.1 µg/mL vs. 1 µg/mL, respectively. IV dosing for N. fowleri is 1.5 mg/kg/day divided in two doses for 3 days, followed by 1 mg/kg/day once daily for 11 days. Intrathecal amphotericin should be given concurrently at 1.5 mg once daily for 2 days and then 1 mg once daily administered every other day for 8 days.

Miltefosine

Miltefosine, originally developed as a cancer treatment, has recently been used as treatment for the protozoal infection leishmaniasis, as well as N. fowleri infections. Miltefosine is an alkylphosphocholine that disrupts the PI3K/Akt/mTOR signaling pathway responsible for cell survival. It is generally well-tolerated, with loss of appetite, diarrhea, nausea and vomiting being the most common side effects. Interestingly, due to miltefosine’s extended half-life, it can take up to 28 days to reach peak concentrations in the body. Miltefosine has shown in vitro activity against N. fowleri prior to being used successfully to treat a 12-year-old patient. Its effect may be due, in part, to an inflammatory activity, as well as activity against the organism. Dosing for miltefosine is weight-based; the 50-mg tablets are given twice daily for patients under 45 kg and three times daily for patients over 45 kg. Providers can call the CDC Emergency Operations Center at (770) 488-7100 to receive the drug.

This photomicrograph depicts histopathologic characteristics associated with a case of amebic meningoencephalitis due to Naegleria fowleri parasites.

As the reporting of N. fowleri infections increases, the four surviving patients have given us insight into a successful treatment regimen. Until new therapies have been further investigated, early identification, intracranial pressure management, and the combination of antifungals, azithromycin, steroids and miltefosine will continue to be recommended for patient survival.

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For more information:
Ashley Schuler, PharmD, is a PGY1 pharmacy practice resident at Denver Health Medical Center.
Kati Shihadeh, PharmD, is a clinical pharmacy specialist in infectious diseases at Denver Health Medical Center. Shihadeh can be reached at katherine.shihadeh@dhha.org.

Disclosures: Schuler and Shihadeh report no relevant financial disclosures.