Primary amoebic meningoencephalitis medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Overview

Considering the the high mortality rate of primary amoebic meningoencephalitis, unusually non-suggestive symptomology of the early-stage disease, and necessity of microbial culture of the cerebrospinal fluid to effect a positive diagnosis, it has been suggested that physicians should give an array of antimicrobial drugs, including the drugs used to treat amoebic encephalitis, before the disease is actually confirmed in order to increase the number of survivors. However, administering several of those drugs at once (or even some of them known to treat the condition) is often very dangerous and unpleasant for the patient.

Medical Therapy

• Admit patients with primary amoebic meningoencephalitis to the intensive care unit (ICU) for intensive monitoring and treatment. The current standard treatment is prompt intravenous administration of heroic doses of amphotericin B, a systemic antifungal that is one of the few effective treatments for systemic infections of protozoal parasitic diseases (such as leishmaniasis and toxoplasmosis).

• The success rate in treating PAM is usually quite poor, since by the time of definitive diagnosis most patients have already manifested signs of terminal cerebral necrosis. Even if definitive diagnosis is effected early enough to allow for a course of medication, amphotericin B also causes significant and permanent nephrotoxicity in the doses necessary to quickly halt the progress of the amoebae through the brain.

• Rifampicin has also been used with amphotericin B in successful treatment. However, there is some evidence that it does not effectively inhibit Naegleria growth.

• The successful use of a combination regimen that includes one amebicidal drug (miltefosine) along with two amebistatic drugs capable of crossing the blood brain barrier (fluconazole and albendazole) provides hope for attaining clinical cure for an otherwise lethal condition.

• There is preclinical evidence that the relatively safe, inexpensive, and widely available phenothiazine antipsychotic chlorpromazine is a highly efficacious amebicide against N. fowleri, with laboratory animal survival rates nearly double those receiving treatment with amphotericin B. The mechanism of action is possibly the inhibition of the nfa1 and Mp2CL5 genes, found only in pathogenic strains of N. fowleri, which are involved in amoebic phagocytosis and regulation of cellular growth, respectively.

• There have been two well-documented survivors (one from the US in 1979 and one from Mexico in 2003) who received the following combination of three drugs successfully (in addition to steroids to control cerebral edema):

1. Amphotericin B (IV +/- intrathecal): (one patient received amphotericin B [AMB] for 14 days and the other patient received it for 9 days). 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. AMB methyl ester was also found to be less effective in the mouse model. Because of the extremely poor prognosis of Naegleria fowleri infection, it’s worth considering aggressive treatment.

2. Rifampicin (oral): 10 mg/kg/day (one survivor received this dosage in three divided doses for 9 days; the other received it every 24 hours for 1 month)

3. Fluconazole (IV or oral): 10 mg/kg/day (one survivor initially received this dosage IV every 24 hours but fluconazole was later switched to oral administration because the hospital ran out of IV stock)
or
Miconazole (IV): 350 mg per square meter of body-surface area per day in three divided doses (one survivor received this regimen for 9 days but miconazole is no longer available in the United States).

• CDC also recommends the use of azithromycin. Azithromycin has both in vitro and in vivo (mouse model) efficacy against Naegleria fowleri and appears to be synergistic when administered with AMB. Therefore, azithromycin may be tried as an adjunct to AMB.