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Background Acanthamoeba spp. is the causative agent of Acanthamoeba keratitis and granulomatous amoebic encephalitis. Strathclyde minor groove binders (S-MGBs) are a promising new class of anti-infective agent that have been shown to be effective against many infectious organisms. Objectives To synthesize and evaluate the anti- Acanthamoeba activity of a panel of S-MGBs, and therefore determine the potential of this class for further development. Methods A panel of 12 S-MGBs was synthesized and anti- Acanthamoeba activity was determined using an alamarBlue™-based trophocidal assay against Acanthamoeba castellanii. Cross-screening against Trypanosoma brucei brucei , Staphylococcus aureus and Escherichia coli was used to investigate selective potency. Cytotoxicity against HEK293 cells allowed for selective toxicity to be measured. DNA binding studies were carried out using native mass spectrometry and DNA thermal shift assays. Results and discussion S-MGB-241 has an IC50 of 6.6 µM against A. castellanii , comparable to the clinically used miltefosine (5.6 µM) and negligible activity against the other organisms. It was also found to have an IC50 > 100 µM against HEK293 cells, demonstrating low cytotoxicity. S-MGB-241 binds to DNA as a dimer, albeit weakly compared to other S-MGBs previously studied. This was confirmed by DNA thermal shift assay with a Δ T m = 1 ± 0.1°C. Conclusions Together, these data provide confidence that S-MGBs can be further optimized to generate new, potent treatments for Acanthameoba spp. infections. In particular, S-MGB-241, has been identified as a 'hit' compound that is selectively active against A. castellanii , providing a starting point from which to begin optimization of DNA binding and potency. [ABSTRACT FROM AUTHOR]

A patient in California, USA, with rare and usually fatal Balamuthia mandrillaris granulomatous amebic encephalitis survived after receiving treatment with a regimen that included the repurposed drug nitroxoline. Nitroxoline, which is a quinolone typically used to treat urinary tract infections, was identified in a screen for drugs with amebicidal activity against Balamuthia.

We describe 10 patients with nonkeratitis Acanthamoeba infection who reported performing nasal rinsing before becoming ill. All were immunocompromised, 7 had chronic sinusitis, and many used tap water for nasal rinsing. Immunocompromised persons should be educated about safe nasal rinsing to prevent free-living ameba infections.

A patient in California, USA, with rare and usually fatal Balamuthia mandrillaris granulomatous amebic encephalitis survived after receiving treatment with a regimen that included the repurposed drug nitroxoline. Nitroxoline, which is a quinolone typically used to treat urinary tract infections, was identified in a screen for drugs with amebicidal activity against Balamuthia.

The report of death of a person from amebic meningoencephalitis, the proverbial "brain-eating ameba," Naegleria fowleri, acquired in a state park lake in Iowa in July 2022 has once again raised the seasonal alarms about this pathogen. While exceptionally rare, its nearly universal fatality rate has panicked the public and made for good copy for the news media. This review will address free-living ameba that have been identified as causing CNS invasion in man, namely, Naegleria fowleri, Acanthamoeba species, Balamuthia mandrillaris, and Sappinia diploidea (Table 1). Of note, several Acanthamoeba spp. and Balamuthia mandrillaris may also be associated with localized extra-CNS infections in individuals who are immunocompetent and disseminated disease in immunocompromised hosts. These ameba are unique from other protozoa in that they are free-living, have no known insect vector, do not result in a human carrier state, and are typically unassociated with poor sanitation. Table 1 Free-living ameba that have been identified as causing CNS invasion in man, namely, Naegleria fowleri, Acanthamoeba species, Balamuthia mandrillaris, and Sappinia diploidea Entity Pathogenic ameba Predisposing disorders Portal of entry Incubation period Clinical features Radiographic findings CSF finding Diagnostic measures Primary amebic meningoencephalitis Naegleria fowleri; N. australiensis; N. italica Previously healthy children or young adults Olfactory epithelium 2–14 days (average 5 days) Headache, fever, altered mental status, meningeal signs; seizures Brain edema; meningeal enhancement; hydrocephalus; basal ganglia infarctions Increased opening pressure; neutrophilic pleocytosis (~ 1000 cells/cu mm); low glucose Brain biopsy, CSF wet prep, IIF culture or PCR Granulomatous amebic encephalitis Acanthamoeba spp.; Balamuthia mandrillaris; Sappinia diploidea Typically, immunocompromised individual Skin sinuses; olfactory epithelium respiratory tract Weeks to months Headache; altered mental status seizures, focal neurological findings Focal parenchymal lesions with edema; hemorrhagic infarctions; meningeal enhancement Generally, LP contraindicated; when performed lymphocytic pleocytosis; increased protein; low glucose Brain biopsy, CSF culture, wet prep, IIF, or PCR IIF indirect immunofluorescence, LP lumbar puncture, PCR polymerase chain reaction [ABSTRACT FROM AUTHOR]

An 82‐year‐old man, who was healthy and had worked as a farmer, experienced worsening neurological symptoms over a seven‐month period, which eventually caused his death. Multiple fluctuating brain lesions were detected radiographically. Clinically, sarcoidosis was ranked high among the differential diagnoses because of the presence of skin lesions showing granulomatous inflammation, confirmed by biopsy. The patient's cerebrospinal fluid was also examined, but no definitive diagnosis was made while he was alive. An autopsy revealed multiple granulomatous amebic encephalitis lesions in the brain. Genetic and immunohistochemical analyses identified Balamuthia (B.) mandrillaris, a free‐living ameba, which resides in soil and fresh water, as the causative organism. A retrospective examination revealed B. mandrillaris in the biopsied skin as well as cerebrospinal fluid, strongly suggesting that the ameba had spread into the brain percutaneously. Few studies have detailed the cutaneous pathology of B. mandrillaris infections. In general, granulomatous amebic encephalitis is extremely difficult to diagnose without autopsy, but the present case provides a clue that could allow similar cases to be diagnosed earlier; that is, the presence of skin lesions. [ABSTRACT FROM AUTHOR]

ABSTRACTBalamuthia amoebic encephalitis has a subacute-to-chronic course and is almost invariably fatal owing to delayed diagnosis and a lack of effective therapy. Here, we report a 13-year-old girl with cutaneous lesions and multifocal granulomatous encephalitis. The patient underwent a series of tests and was suspected as having tuberculosis. She was treated with various empiric therapies without improvement. She was finally correctly diagnosed via next-generation sequencing of the cerebrospinal fluid. The patient deteriorated rapidly and died 2 months after being diagnosed with Balamuthia mandrillaris encephalitis. This study highlights the important clinical significance of next-generation sequencing, which provides better diagnostic testing for unexplained paediatric encephalitis, especially that caused by rare or emerging pathogens.

Balamuthia mandrillaris is an opportunistic, free-living ameba that is pathogenic to humans. It has a worldwide distribution but is mainly detected in warmer regions. Balamuthia infections are rare but have been reported in both immunocompetent and immunocompromised individuals of all ages. B. mandrillaris can enter through wounds on the skin or the nose and cause cutaneous lesions and the usually fatal Balamuthia amebic encephalitis (BAE). Infection usually spreads from the lungs or through nerve fibers, and attacks the central nervous system, forming granulomatous lesions and necrosis in the brain. Balamuthia infection is usually chronic, and patients initially present with nonspecific symptoms, including headache, nausea, myalgia, and low-grade fever. As the disease progresses, the patient becomes paralyzed and comatose, often leading to death. Lack of knowledge of predisposing factors, specific treatment, and standardized detection tools have resulted in a nearly cent percent fatality rate. Although only about 200 cases have been reported worldwide since its characterization in the 1990s, the number of reported cases has increased over the years. BAE is an emerging disease and a major health concern. Few patients have survived Balamuthia infections with antimicrobial treatment that has largely been empirical. Early diagnosis is the key and requires familiarity with the disease and a high degree of suspicion on the part of the diagnostician. There are currently no specific treatment and prevention recommendations. This review highlights our current understanding of B. mandrillaris in terms of its pathogenicity, genomics, and novel diagnostic and therapeutic approaches against BAE infections. [ABSTRACT FROM AUTHOR]

We describe 10 patients with nonkeratitis Acanthamoeba infection who reported performing nasal rinsing before becoming ill. All were immunocompromised, 7 had chronic sinusitis, and many used tap water for nasal rinsing. Immunocompromised persons should be educated about safe nasal rinsing to prevent free-living ameba infections.

Parasitic diseases affect more than one billion people worldwide, and most of them are chronic conditions in which the treatment and prevention are difficult. The appearance of granulomas, defined as organized and compact structures of macrophages and other immune cells, during various parasitic diseases is frequent, since these structures will only form when individual immune cells do not control the invading agent. Th2-typering various parasitic diseases are frequent, since these structures will only form when individual immune cells do not control the invading agent. The characterization of granulomas in different parasitic diseases, as well as recent findings in this field, is discussed in this review, in order to understand the significance of the granuloma and its modulation in the host–parasite interaction and in the immune, pathological, and parasitological aspects of this interaction. The parasitic granulomatous diseases granulomatous amebic encephalitis, toxoplasmosis, leishmaniasis, neurocysticercosis, and schistosomiasis mansoni are discussed as well as the mechanistic and dynamical aspects of the infectious granulomas. [ABSTRACT FROM AUTHOR]

Acanthamoeba spp. and Balamuthia mandrillaris are free-living amebae known to cause disseminated and fatal central nervous system dysfunction which manifests as granulomatous amebic encephalitis (GAE) with exceedingly rare frequency. We report two lethal cases of infection with free-living amebae: an acute case of Acanthamoeba spp. infection in an immunocompromised female and a subacute case of B. mandrillaris in a Hispanic male. The Acanthamoeba spp. infection presented with an atypical lesion in the thalamus that caused rapid deterioration of the patient while the case of B. mandrillaris had a prolonged clinical course with multifocal lesions beginning in the frontal lobe. Cerebrospinal fluid results were non-specific in both cases, however, post-mortem histology demonstrated the presence of trophozoites along a perivascular distribution of necrosis and infiltrate composed primarily of neutrophils. In addition to detailing the clinical presentations of these infrequent amebic infections, we offer insight into the difficulties surrounding their diagnoses in order to aid the clinician in accurate and timely identification. [ABSTRACT FROM AUTHOR]

Objectives: Pathogenic free-living amebae (FLAs) cause skin, ocular, and central nervous system (CNS) infections with significant morbidity and mortality. Diagnosis of FLA infections by pathologic examination of tissue sections can be aided using molecular assays. This study investigated the performance characteristics of a multiplex real-time polymerase chain reaction (PCR) assay (FLA-PCR) for detection and differentiation of FLAs in clinical specimens.Methods: FLA-PCR was performed on 39 human specimens comprising one cutaneous, 14 corneal, and 24 CNS formalin-fixed, paraffin-embedded (FFPE) tissues with a histopathologic diagnosis of FLA infection and four CNS FFPE tissues with inflammation but no evidence of FLAs. In addition, clinical specificity and assay limit of detection were determined.Results: FLA detection sensitivities ranged from 79% to 84% in FFPE tissues. No cross-reactivity was observed.Conclusions: While sensitivity is limited, FLA-PCR assay may serve as a useful adjunct for detection or confirmation of FLA infections in FFPE tissues. [ABSTRACT FROM AUTHOR]

Background Balamuthia mandrillaris is a free-living ameba that causes rare, nearly always fatal disease in humans and animals worldwide. B. mandrillaris has been isolated from soil, dust, and water. Initial entry of Balamuthia into the body is likely via the skin or lungs. To date, only individual case reports and small case series have been published. Methods The Centers for Disease Control and Prevention (CDC) maintains a free-living ameba (FLA) registry and laboratory. To be entered into the registry, a Balamuthia case must be laboratory-confirmed. Several sources were used to complete entries in the registry, including case report forms, CDC laboratory results, published case reports, and media information. SAS© version 9.3 software was used to calculate descriptive statistics and frequencies. Results We identified 109 case reports of Balamuthia disease between 1974 and 2016. Most (99%) had encephalitis. The median age was 36 years (range 4 months to 91 years). Males accounted for 68% of the case patients. California had the highest number of case reports, followed by Texas and Arizona. Hispanics constituted 55% for those with documented ethnicity. Exposure to soil was commonly reported. Among those with a known outcome, 90% of patients died. Conclusions Balamuthia disease in the United States is characterized by a highly fatal encephalitis that affects patients of all ages. Hispanics were disproportionately affected. The southwest region of the United States reported the most cases. Clinician awareness of Balamuthia as a cause of encephalitis might lead to earlier diagnosis and initiation of treatment, resulting in better outcomes. [ABSTRACT FROM AUTHOR]

Acanthamoeba may lead to granulomatous amebic encephalitis (GAE) with high mortality rates generally in patients with immunosupression and/or chronic disease. Here, we present a rare GAE case, who was a previously healthy child. A Georgian 9 year old boy presented with focal seizure on his left arm and confusion. Since computed tomography (CT) demonstrated hypodense lesion on right occipital lobe, brain biopsy was performed. Histopathological examination of the biopsy material revealed Acanthamoeba cysts and trophozoites together with granulomatous inflammation. The patient, who had no clinical and laboratory findings consistent with immunedeficiency, was diagnosed as GAE. He was treated with a combination drug therapy. Even if it is very rare, amebic meningoencephalitis may also be seen in immunocompetent children, as in our case. Definitive diagnosis is made by microbiological and histopathological examination of brain biopsy material. [ABSTRACT FROM AUTHOR]

Case description: A 38-year-old man presented with headaches and generalized weakness. He was found to have AIDS; a ring-enhancing central nervous system lesion was found on brain imaging and he had elevated serum Toxoplasma gondii IgG levels. A diagnosis of presumptive toxoplasma encephalitis was made and he received antiretrovirals and antitoxoplasma therapy for 4 years. Intermittent headaches and evidence of disease progression on neuroimaging warranted further evaluation and cerebrospinal fluid analysis revealed amebic forms on hematoxylin and eosin staining and positive polymerase chain reaction testing for Acanthamoeba spp. He was placed on miltefosine, fluconazole, trimethoprim-sulfamethoxazole and flucytosine for 7 months. Five months after therapy discontinuation he remains asymptomatic and is taking only antiretroviral therapy. Conclusion: This is the first report of a patient with AIDS and granulomatous amebic encephalitis who survived with medical therapy only. [ABSTRACT FROM AUTHOR]

Granulomatous amebic encephalitis is a life-threatening central nervous system (CNS) infection caused by the free-living amoebae Acanthamoeba spp., Balamuthia mandrillaris and Sappinia pedata. The disease has a subacute to chronic onset affecting commonly the immunocompromised population with high mortality rate. The diagnosis of this disease entity requires high suspicion with appropriate sample collection and testing by the laboratory experts. Radiological investigations are nonspecific and commonly confused with CNS tuberculosis, neurocysticercosis, disseminated encephalomyelitis, viral encephalitis etc., delaying the accurate diagnosis of these cases. Early diagnosis plays a crucial role in the survival of these cases since appropriate management can be initiated. No single drug is effective; hence multiple antibiotics targeting various proteins or receptors are required for successful treatment. A combination of surgical and medical interventions involving multiple specialty experts is required to prevent death and morbidity in survivors. [ABSTRACT FROM AUTHOR]

Balamuthia mandrillaris is one of the 4 amebas in fresh water and soil that cause diseases in humans. Granulomatous amebic encephalitis (GAE), caused by B. mandrillaris, is a rare but life-threatening condition. A 4-year-old, previously healthy, Thai girl presented with progressive headache and ataxia for over a month. Neuroimaging studies showed an infiltrative mass at the right cerebellar hemisphere mimicking a malignant cerebellar tumor. The pathological finding after total mass removal revealed severe necrotizing inflammation, with presence of scattered amebic trophozoites. Cerebrospinal fluid (CSF) obtained from lumbar puncture showed evidence of non-specific inflammation without identifiable organisms. A combination of pentamidine, sulfasalazine, fluconazole, and clarithromycin had been initiated promptly before PCR confirmed the diagnosis of Balamuthia amebic encephalitis (BAE). The patient showed initial improvement after the surgery and combined medical treatment, but gradually deteriorated and died of multiple organ failure within 46 days upon admission despite early diagnosis and treatment. In addition to the case, 10 survivors of BAE reported in the PubMed database were briefly reviewed in an attempt to identify the possible factors leading to survival of the patients diagnosed with this rare disease. [ABSTRACT FROM AUTHOR]

Background: Amebic encephalitis (granulomatous amebic encephalitis, GAE) an extremely rare disease occurring in immunocompromised patients. Presentation and early imaging findings are nonspecific. In GAE, enhancement may or may not be seen on imaging studies despite the presence of an aggressive, necrotizing, parasitic infection. Case Description: The patient was a 79-year-old man with ill-defined autoimmune hepatitis. He was on mild immunosuppression with 6-MP and low-dose prednisone. He presented with an acute febrile illness and obtundation. Imaging revealed a nonenhancing mass lesion of the frontal lobe. The patient briefly improved on high-dose steroids, then deteriorated again, with repeat imaging showing enlargement of the edematous brain lesion and herniation. The patient underwent craniotomy for evacuation of a necrotic brain lesion. His condition did not improve. Frozen section revealed only necrosis. Permanent pathology revealed GAE caused by Acanthamoeba. Conclusion: Neurosurgeons should remain aware of this rare disease. Imaging is variable and may not show enhancement or necrosis despite large areas of parasitic infection. [ABSTRACT FROM AUTHOR]

Abstract: Some free-living amoebae, including some species of the genus Acanthamoeba, can cause infections in humans and animals. These organisms are known to cause granulomatous amebic encephalitis (GAE) in predominantly immune-deficient persons. In the present study, we isolated a potentially human pathogenic Acanthamoeba isolate originating from a public heated indoor swimming pool in Switzerland. The amoebae, thermophilically preselected by culture at 37°C, subsequently displayed a high thermotolerance, being able to grow at 42°C, and a marked cytotoxicity, based on a co-culture system using the murine cell line L929. Intranasal infection of Rag2-immunodeficient mice resulted in the death of all animals within 24 days. Histopathology of brains and lungs revealed marked tissue necrosis and hemorrhagic lesions going along with massive proliferation of amoebae. PCR and sequence analysis, based on 18S rDNA, identified the agent as Acanthamoeba lenticulata. In summary, the present study reports on an Acanthamoeba isolate from a heated swimming pool suggestive of being potentially pathogenic to immunocompromised persons. [Copyright &y& Elsevier]

Microscopic observations of live cultures of the pathogenic ameba Balamuthia mandrillaris and mammalian cells showed that amebic feeding involved the invasion of the pseudopodia, and/or the whole ameba into the cells. The ameba, recognized by their size and flow of organelles in the cytosol, was seen to extend the tip of a pseudopodium into the cytoplasm of a cell where it moved about leaving visible damage when retracted. In rounded cells, whole amebas were seen to enter into and move around before exiting a cell and then remain quiescent for hours. The invaded mammalian cells retained their turgidity and excluded vital dyes until only their denuded nuclei remained. The cytoplasm of the cells was consumed first, then the nuclei, but not their mitotic chromosomes. The feeding pattern of four isolates of B. mandrillaris, two from humans and two from soil samples, was by amebic invasion into the mammalian cells. The resulting ameba population included cysts, amebas on the surface, and free-floating amebas as individuals or in dense-packed clusters. There was no morphologic indication of a cytopathic change in the mammalian cells before their invasion by the amebas. Feeding by cell invasion is a distinctive feature of B. mandrillaris. [ABSTRACT FROM AUTHOR]

In the literature, variable enhanced patterns in cases of granulomatous amebic encephalitis (GAE) have been reported. The reason for this variety is still unknown. We report a case of GAE in whom serial images showed different enhanced patterns as the lesions evolved. The enhanced pattern was nodular or gyriform at its early stage, became ring-like as the lesions enlarged and at its late stage, developed into a heterogeneous pattern. We concluded that the variable enhanced patterns seen in GAE might correspond to the evolution of the lesions. Realizing the serial changes may help us in the early diagnosis and treatment of this fatal disease. [Copyright &y& Elsevier]

Balamuthia amoebic encephalitis has a subacute-to-chronic course and is almost invariably fatal owing to delayed diagnosis and a lack of effective therapy. Here, we report a 13-year-old girl with cutaneous lesions and multifocal granulomatous encephalitis. The patient underwent a series of tests and was suspected as having tuberculosis. She was treated with various empiric therapies without improvement. She was finally correctly diagnosed via next-generation sequencing of the cerebrospinal fluid. The patient deteriorated rapidly and died 2 months after being diagnosed with Balamuthia mandrillaris encephalitis. This study highlights the important clinical significance of next-generation sequencing, which provides better diagnostic testing for unexplained paediatric encephalitis, especially that caused by rare or emerging pathogens.