Naegleria fowleri: Pathogenesis, Diagnosis, and Treatment Options

ABSTRACTNaegleria fowlerihas generated tremendous media attention over the last 5 years due to several high-profile cases. Several of these cases were followed very closely by the general public.N. fowleriis a eukaryotic, free-living amoeba belonging to the phylum Percolozoa.Naegleriaamoebae are ubiquitous in the environment, being found in soil and bodies of freshwater, and feed on bacteria found in those locations. WhileN. fowleriinfection appears to be quite rare compared to other diseases, the clinical manifestations of primary amoebic meningoencephalitis are devastating and nearly always fatal. Due to the rarity ofN. fowleriinfections in humans, there are no clinical trials to date that assess the efficacy of one treatment regimen over another. Most of the information regarding medication efficacy is based on either case reports orin vitrostudies. This review will discuss the pathogenesis, diagnosis, pharmacotherapy, and prevention ofN. fowleriinfections in humans, including a brief review of all survivor cases in North America.

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Primary Amoebic Meningoencephalitis by Naegleria fowleri: Pathogenesis and Treatments

Biomolecules ◽

10.3390/biom11091320 ◽

2021 ◽

Vol 11 (9) ◽

pp. 1320 ◽

Cited By ~ 1

Author(s):

Andrea Güémez ◽

Elisa García

Keyword(s):

Molecular Mechanisms ◽

Case Reports ◽

Naegleria Fowleri ◽

Initial Exposure ◽

Immunomodulatory Agents ◽

Primary Amoebic Meningoencephalitis ◽

The Central Nervous System ◽

Nægleria Fowleri ◽

Amoebic Meningoencephalitis ◽

The Brain

Naegleria fowleri is a free-living amoeba (FLA) that is commonly known as the “brain-eating amoeba.” This parasite can invade the central nervous system (CNS), causing an acute and fulminating infection known as primary amoebic meningoencephalitis (PAM). Even though PAM is characterized by low morbidity, it has shown a mortality rate of 98%, usually causing death in less than two weeks after the initial exposure. This review summarizes the most recent information about N. fowleri, its pathogenic molecular mechanisms, and the neuropathological processes implicated. Additionally, this review includes the main therapeutic strategies described in case reports and preclinical studies, including the possible use of immunomodulatory agents to decrease neurological damage.

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Brain-Eating Amoebae: Predilection Sites in the Brain and Disease Outcome

Journal of Clinical Microbiology ◽

10.1128/jcm.02300-16 ◽

2017 ◽

Vol 55 (7) ◽

pp. 1989-1997 ◽

Cited By ~ 31

Author(s):

Timothy Yu Yee Ong ◽

Naveed Ahmed Khan ◽

Ruqaiyyah Siddiqui

Keyword(s):

Case Reports ◽

Treatment Options ◽

Acute Infection ◽

Content Type ◽

Disease Outcomes ◽

Granulomatous Amoebic Encephalitis ◽

Causative Agents ◽

Diagnostic Modalities ◽

Amoebic Meningoencephalitis ◽

The Brain

ABSTRACTAcanthamoebaspp. andBalamuthia mandrillarisare causative agents of granulomatous amoebic encephalitis (GAE), whileNaegleria fowlericauses primary amoebic meningoencephalitis (PAM). PAM is an acute infection that lasts a few days, while GAE is a chronic to subacute infection that can last up to several months. Here, we present a literature review of 86 case reports from 1968 to 2016, in order to explore the affinity of these amoebae for particular sites of the brain, diagnostic modalities, treatment options, and disease outcomes in a comparative manner.

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Bis-Benzimidazole Hits against Naegleria fowleri Discovered with New High-Throughput Screens

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05122-14 ◽

2015 ◽

Vol 59 (4) ◽

pp. 2037-2044 ◽

Cited By ~ 23

Author(s):

Christopher A. Rice ◽

Beatrice L. Colon ◽

Mehmet Alp ◽

Hakan Göker ◽

David W. Boykin ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

High Throughput ◽

Lead Optimization ◽

New Drugs ◽

Naegleria Fowleri ◽

Onset Of Action ◽

Content Type ◽

Nægleria Fowleri

ABSTRACTNaegleria fowleriis a pathogenic free-living amoeba (FLA) that causes an acute fatal disease known as primary amoebic meningoencephalitis (PAM). The major problem for infections with any pathogenic FLA is a lack of effective therapeutics, since PAM has a case mortality rate approaching 99%. Clearly, new drugs that are potent and have rapid onset of action are needed to enhance the treatment regimens for PAM. Diamidines have demonstrated potency against multiple pathogens, including FLA, and are known to cross the blood-brain barrier to cure other protozoan diseases of the central nervous system. Therefore, amidino derivatives serve as an important chemotype for discovery of new drugs. In this study, we validated two newin vitroassays suitable for medium- or high-throughput drug discovery and used these forN. fowleri. We next screened over 150 amidino derivatives of multiple structural classes and identified two hit series with nM potency that are suitable for further lead optimization as new drugs for this neglected disease. These include both mono- and diamidino derivatives, with the most potent compound (DB173) having a 50% inhibitory concentration (IC50) of 177 nM. Similarly, we identified 10 additional analogues with IC50s of <1 μM, with many of these having reasonable selectivity indices. The most potent hits were >500 times more potent than pentamidine. In summary, the mono- and diamidino derivatives offer potential for lead optimization to develop new drugs to treat central nervous system infections withN. fowleri.

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Enzymatic and Structural Characterization of the Naegleria fowleri Glucokinase

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02410-18 ◽

2019 ◽

Vol 63 (5) ◽

Cited By ~ 7

Author(s):

Jillian E. Milanes ◽

Jimmy Suryadi ◽

Jan Abendroth ◽

Wesley C. Van Voorhis ◽

Kayleigh F. Barrett ◽

...

Keyword(s):

Glucose Metabolism ◽

Homo Sapiens ◽

Treatment Options ◽

Amino Acid Identity ◽

Pentose Phosphate ◽

Mammalian Host ◽

Binding Modes ◽

Naegleria Fowleri ◽

Content Type ◽

Nægleria Fowleri

ABSTRACT Infection with the free-living amoeba Naegleria fowleri leads to life-threatening primary amoebic meningoencephalitis. Efficacious treatment options for these infections are limited, and the mortality rate is very high (∼98%). Parasite metabolism may provide suitable targets for therapeutic design. Like most other organisms, glucose metabolism is critical for parasite viability, being required for growth in culture. The first enzyme required for glucose metabolism is typically a hexokinase (HK), which transfers a phosphate from ATP to glucose. The products of this enzyme are required for both glycolysis and the pentose phosphate pathway. However, the N. fowleri genome lacks an obvious HK homolog and instead harbors a glucokinase (Glck). The N. fowleri Glck (NfGlck) shares limited (25%) amino acid identity with the mammalian host enzyme (Homo sapiens Glck), suggesting that parasite-specific inhibitors with anti-amoeba activity can be generated. Following heterologous expression, NfGlck was found to have a limited hexose substrate range, with the greatest activity observed with glucose. The enzyme had apparent Km values of 42.5 ± 7.3 μM and 141.6 ± 9.9 μM for glucose and ATP, respectively. The NfGlck structure was determined and refined to 2.2-Å resolution, revealing that the enzyme shares greatest structural similarity with the Trypanosoma cruzi Glck. These similarities include binding modes and binding environments for substrates. To identify inhibitors of NfGlck, we screened a small collection of inhibitors of glucose-phosphorylating enzymes and identified several small molecules with 50% inhibitory concentration values of <1 μM that may prove useful as hit chemotypes for further leads and therapeutic development against N. fowleri.

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Primary Amoebic Meningoencephalitis Preventive Nose Plugs: Prophylaxis Against Naegleria fowleri

Journal of Medical Devices ◽

10.1115/1.4032106 ◽

2016 ◽

Vol 10 (1) ◽

Author(s):

Abdul Mannan Baig

Keyword(s):

Naegleria Fowleri ◽

Free Living ◽

Primary Amoebic Meningoencephalitis ◽

Free Living Amoeba ◽

History Of ◽

Nægleria Fowleri ◽

Water Sports ◽

Amoebic Meningoencephalitis

Naegleria fowleri is a free-living amoeba; it is a protist pathogen that is known to cause a fatal encephalitis in humans known as “primary amoebic meningoencephalitis” (PAM). The peak season for the cases admitted to the hospital is in the summers, and all the reported cases have a history of exposure to the warm waters. Mostly, PAM is reported in recent swimmers and people who perform ablution and/or nasal cleansing. Much has been done for vaccination and treatment without any success in past 60 years, but the mortality has remained 99%. Here, we propose a prophylaxis for this disease by introducing a device “Naegleriopel.” This device is noninvasive and requires insertion into the nostrils at times of swimming or water sports related activities. This device, made up of synthetic plastic or silicone, could be adapted to the contours of the interior of the nose. It is expected to reduce the sporadic and seasonal incidences of PAM.

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Laurinterol from Laurencia johnstonii eliminates Naegleria fowleri triggering PCD by inhibition of ATPases

Scientific Reports ◽

10.1038/s41598-020-74729-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Iñigo Arberas-Jiménez ◽

Sara García-Davis ◽

Aitor Rizo-Liendo ◽

Ines Sifaoui ◽

María Reyes-Batlle ◽

...

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Treatment Options ◽

Opportunistic Pathogen ◽

Current Treatment ◽

Ion Pump ◽

Naegleria Fowleri ◽

Trophozoite Stage ◽

Nægleria Fowleri

Abstract Primary amoebic encephalitis (PAM) is a lethal disease caused by the opportunistic pathogen, Naegleria fowleri. This amoebic species is able to live freely in warm aquatic habitats and to infect children and young adults when they perform risk activities in these water bodies such as swimming or splashing. Besides the need to increase awareness of PAM which will allow an early diagnosis, the development of fully effective therapeutic agents is needed. Current treatment options are amphotericin B and miltefosine which are not fully effective and also present toxicity issues. In this study, the in vitro activity of various sesquiterpenes isolated from the red alga Laurencia johnstonii were tested against the trophozoite stage of a strain of Naegleria fowleri. Moreover, the induced effects (apoptotic cell death) of the most active compound, laurinterol (1), was evaluated by measuring DNA condensation, damages at the mitochondrial level, cell membrane disruption and production of reactive oxygen species (ROS). The obtained results demonstrated that laurinterol was able to eliminate the amoebae at concentrations of 13.42 ± 2.57 µM and also to induced programmed cell death (PCD) in the treated amoebae. Moreover, since ATP levels were highly affected and laurinterol has been previously reported as an inhibitor of the Na+/K+-ATPase sodium–potassium ion pump, comparison with known inhibitors of ATPases were carried out. Our results points out that laurinterol was able to inhibit ENA ATPase pump at concentrations 100 times lower than furosemide.

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Treatment of Infections by OXA-48-Producing Enterobacteriaceae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01195-18 ◽

2018 ◽

Vol 62 (11) ◽

Cited By ~ 41

Author(s):

Adam Stewart ◽

Patrick Harris ◽

Andrew Henderson ◽

David Paterson

Keyword(s):

Antimicrobial Agents ◽

Case Reports ◽

Treatment Options ◽

Treatment Success ◽

Intrinsic Activity ◽

Beta Lactamase ◽

Global Public Health ◽

Content Type ◽

Extended Spectrum Beta Lactamase

ABSTRACT Carbapenemase-producing Enterobacteriaceae (CPE) contribute significantly to the global public health threat of antimicrobial resistance. OXA-48 and its variants are unique carbapenemases with low-level hydrolytic activity toward carbapenems but no intrinsic activity against expanded-spectrum cephalosporins. blaOXA-48 is typically located on a plasmid but may also be integrated chromosomally, and this gene has progressively disseminated throughout Europe and the Middle East. Despite the inability of OXA-48-like carbapenemases to hydrolyze expanded-spectrum cephalosporins, pooled isolates demonstrate high variable resistance to ceftazidime and cefepime, likely representing high rates of extended-spectrum beta-lactamase (ESBL) coproduction. In vitro data from pooled studies suggest that avibactam is the most potent beta-lactamase inhibitor when combined with ceftazidime, cefepime, aztreonam, meropenem, or imipenem. Resistance to novel avibactam combinations such as imipenem-avibactam or aztreonam-avibactam has not yet been reported in OXA-48 producers, although only a few clinical isolates have been tested. Although combination therapy is thought to improve the chances of clinical cure and survival in CPE infection, successful outcomes were seen in ∼70% of patients with infections caused by OXA-48-producing Enterobacteriaceae treated with ceftazidime-avibactam monotherapy. A carbapenem in combination with either amikacin or colistin has achieved treatment success in a few case reports. Uncertainty remains regarding the best treatment options and strategies for managing these infections. Newly available antibiotics such as ceftazidime-avibactam show promise; however, recent reports of resistance are concerning. Newer choices of antimicrobial agents will likely be required to combat this problem.

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Effect of Therapeutic Chemical Agents In Vitro and on Experimental Meningoencephalitis Due to Naegleria fowleri

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00197-08 ◽

2008 ◽

Vol 52 (11) ◽

pp. 4010-4016 ◽

Cited By ~ 40

Author(s):

Jong-Hyun Kim ◽

Suk-Yul Jung ◽

Yang-Jin Lee ◽

Kyoung-Ju Song ◽

Daeho Kwon ◽

...

Keyword(s):

Amphotericin B ◽

Survival Rates ◽

Laboratory Animals ◽

Naegleria Fowleri ◽

Time To Death ◽

Nægleria Fowleri ◽

Amoebic Meningoencephalitis ◽

Mean Time

ABSTRACT Naegleria fowleri is a ubiquitous, pathogenic free-living amoeba; it is the most virulent Naegleria species and causes primary amoebic meningoencephalitis (PAME) in laboratory animals and humans. Although amphotericin B is currently the only agent available for the treatment of PAME, it is a very toxic antibiotic and may cause many adverse effects on other organs. In order to find other potentially therapeutic agents for N. fowleri infection, the present study was undertaken to evaluate the in vitro and in vivo efficacies of miltefosine and chlorpromazine against pathogenic N. fowleri. The result showed that the growth of the amoeba was effectively inhibited by treatment with amphotericin B, miltefosine, and chlorpromazine. When N. fowleri trophozoites were treated with amphotericin B, miltefosine, and chlorpromazine, the MICs of the drug were 0.78, 25, and 12.5 μg/ml, respectively, on day 2. In experimental meningoencephalitis of mice that is caused by N. fowleri, the survival rates of mice treated with amphotericin B, miltefosine, and chlorpromazine were 40, 55, and 75%, respectively, during 1 month. The average mean time to death for the amphotericin B, miltefosine, and chlorpromazine treatments was 17.9 days. In this study, the effect of drugs was found to be optimal when 20 mg/kg was administered three times on days 3, 7, and 11. Finally, chlorpromazine had the best therapeutic activity against N. fowleri in vitro and in vivo. Therefore, it may be a more useful therapeutic agent for the treatment of PAME than amphotericin B.

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ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02415-19 ◽

2020 ◽

Vol 64 (6) ◽

Cited By ~ 3

Author(s):

Ørjan Samuelsen ◽

Ove Alexander Høgmoen Åstrand ◽

Christopher Fröhlich ◽

Adam Heikal ◽

Susann Skagseth ◽

...

Keyword(s):

Active Site ◽

Therapeutic Potential ◽

Treatment Options ◽

Carbapenem Resistance ◽

Functional Space ◽

Bactericidal Effect ◽

Gram Negative ◽

Content Type

ABSTRACT Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n = 234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM, and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ∼30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modeling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor that is capable of operating in a functional space not presently filled by any clinically approved compound.

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