Acanthamoeba species

Acanthamoeba can causes disease in immunocompromised and immunocompetent individuals; the first human infections were described in 1958 as the cause of granulomatous amoebic encephalitis (GAE). To date, 23 different sequence types of Acanthamoeba have been reported by the community based on >4% pairwise sequence difference in the Acanthamoeba specific amplifier (ASA) within the 18S rRNA gene sequence. Various genotypes have been more commonly associated with different infections of Acanthamoeba disease; for example, T4 is the most commonly isolated genotype and primarily associated with GAE and Acanthamoeba keratitis, whereas genotypes T1, T10 and T12 are associated with GAE. Genotypes T4, T3 and T11 are more commonly found in Acanthamoeba keratitis infections and more recently genotypes T5 and T17 have been associated with cutaneous amoebiasis. One of the major problems and concerns with all Acanthamoeba infections are that amoebae can encyst into their protective dormant cyst stage and resist treatment within all of the tissues it can infect. Treatment is terminated when the patient’s symptoms improve, however persistent parasites can excyst and cause further pathology and disease. Recrudescence has been reported up to 5 years after initial infection and treatment.

Acanthamoeba keratitis (AK) is an excruciating and debilitating infection of the cornea. It is the most common disease caused by Acanthamoeba species, mainly in association with contact lens contamination, although non-contact lens wearing AK cases have been reported. Diagnosis is challenging and, if not treated aggressively, visual impairment or blindness can occur. Moderately successful treatment, if applied early, has been achieved by using the combinational chemotherapy of 0.02–0.2% chlorhexidine gluconate, 0.02–0.06% polyhexamethylene biguanide (PHMB), and 0.1% propamidine, with or without neomycin, 1% azoles, or other amidines (e.g., 0.1% hexamidine). Depending on the clinical response, chemotherapy with topical agents can vary from months to years. Unfortunately, most of the current chemotherapy agents are cytotoxic to corneal cells and, as an example, at one eye care clinic, approximately 25% of confirmed AK patient’s required therapeutic keratoplasty (corneal transplantation) or in extreme cases enucleation of the eye.

Cutaneous amoebiasis lesions and nasopharyngeal infections caused by various Acanthamoeba species are mainly in immunosuppressed patients such as human immunodeficiency virus (HIV) infections, chemotherapy recipients, those with immunodeficiency syndromes, and transplant recipients. Only 5 cutaneous cases have been reported in immunocompetent patients with a unique case of oste-cutaneous acanthamoebiasis (bone involvement) due to traumatic inoculation through an injury sustained playing sports. All other cases are through Acanthamoeba infecting through cuts or breaks in the skin or via the nasal passage. With a case mortality of ~70% in the absence of GAE and almost always fatal with central nervous system (CNS) involvement, better treatments for successful patient outcomes need to be investigated. There is no clinical agreement or treatment recommendation for cutaneous lesions; rather healthcare providers have depended upon research to decide which agents to use for treating Acanthamoeba infections. Broadly, cutaneous cases have been successfully treated with combinations of amphotericin B, pentamidine isethionate, chlorhexidine gluconate, 5-fluorocytosine, fluconazole, itraconazole, ketoconazole, azithromycin, clarithromycin sulfadiazine, and pyrimethamine, along with the debridement of sinuses in cases of sinusitis.

From skin or lung infections, Acanthamoeba can spread to the CNS through haematogenous dissemination where it can attach, and break down the blood-brain barrier, then infect brain tissue causing granulomatous amoebic encephalitis (GAE). Similarly to PAM, GAE is most commonly diagnosed post mortem, since the clinical symptoms of headache, vomiting, nausea, confusion, fever, ataxia, increased cranial pressure, and seizures that resemble meningitis caused by bacteria or viruses leading to misdiagnosis. GAE is found in patients with preexisting underlying diseases. It has a slower more chronic disease progression of the course of several weeks to months before clinical symptoms arise and an accurate diagnosis can be made. GAE has a > 90% mortality rate. Currently, a small number of successful outcomes have resulted from treatment with a mixture of combinational chemotherapies including antifungal azoles (clotrimazole, miconazole, ketoconazole, fluconazole, itraconazole, or voriconazole), antifungals (amphotericin B, flucytosine, caspofungin, pentamidine isethionate, hydroxystilbamidine, 5-fluorocytosine), antibiotics (azithromycin, rifampin, trimethoprim/sulfamethoxazole, sulfadiazine, chloramphenicol, paromomycin, polymyxin) and more recently miltefosine.

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.