Naegleria fowleri, the causative agent of primary amoebic meningoencephalitis (PAM), was first discovered to be a human pathogen by Fowler and Carter after four fatal infections from 1961–1965 in Adelaide, Australia. From 1962–2022, 157 cases have been reported in the United States (US), with several hundreds of cases recorded around the world. Naegleria, being thermophilic, thrives in warm fresh waters where it can exist as one of three forms: the trophozoite form (active feeding stage), flagellated form (motile swimming stage), or as a cyst form (protective dormant stage). The trophozoite is thought to be the only infective stage of N. fowleri. PAM is not a notifiable disease in the US, and due to common misdiagnosis as bacterial or viral meningitis, the number of reported cases is likely to be a significant underestimate of disease burden globally. PAM is commonly associated with recreational water activities in which water is inhaled into the nasal cavity. For example, swimming, jumping into water without holding the nose or wearing a nose clip, water sports (wake boarding, water skiing, jet skiing, and white water rafting), and more recently increased use of neti pots for sinus/nasal irrigation or religious practice of nasal cleansing, are all risk factors for PAM. Once N. fowleri enters the nasal cavity, the amoebae traverse the cribriform plate the olfactory nerve to reach the frontal cerebral cortex of the brain where they cause hemorrhagic meningoencephalitis with the classical PAM symptoms of severe headache, stiff neck, hallucinations, seizures, coma, and, in 97% of cases, death. With gradually increasing awareness and better diagnostic tools (real-time PCR, LAMP assays, antigen detection and serological testing) more cases are being diagnosed faster. Key to the few instances of PAM survival is early diagnosis and a combinational treatment regimen that includes amphotericin B, azithromycin, fluconazole, miltefosine, rifampin and dexamethasone. Miltefosine, a breast cancer chemotherapeutic agent and anti-leishmanial drug, was repurposed for treatment of FLA diseases after the discovery of activity in in vitro and in vivo models. Several recent PAM survival cases included inducement of therapeutic hypothermia (cooling of the core body temperature to 32–34°C) to better manage intracranial pressure; this technique also reduces reactive oxygen and nitrogen species, neural apoptosis, and proinflammatory cytokine levels, all of which increase brain injury through hyperinflammation.
These high mortality rates indicate that there is a significant unmet medical need to discover new drugs that are efficacious against Naegleria, Acanthamoeba and Balamuthia trophozoites and/or cysts and have increased selectivity to the pathogen over infected dead-end host. Given the lack of major pharmaceutical company involvement in discovery of new drugs for the diseases caused by amoebae, our drug repurposing and development approaches are vital to overcome the unmet medical needs.
