ACTIVITIES OF THERAPEUTIC AGENTS AGAINST NAEGLERIA FOWLERI IN VITRO AND IN A MOUSE MODEL OF PRIMARY AMEBIC MENINGOENCEPHALITIS

2003 ◽  
Vol 89 (4) ◽  
pp. 837-842 ◽  
Author(s):  
Shannon M. Goswick ◽  
George M. Brenner
Keyword(s):  
Mouse Model ◽  
Therapeutic Agents ◽  
Naegleria Fowleri ◽  
Nægleria Fowleri ◽  
Primary Amebic Meningoencephalitis

scholarly journals Synergistic Activities of Azithromycin and Amphotericin B against Naegleria fowleri In Vitro and in a Mouse Model of Primary Amebic Meningoencephalitis

2006 ◽  
Vol 51 (1) ◽  
pp. 23-27 ◽  
Author(s):  
Shannon M. Soltow ◽  
George M. Brenner
Keyword(s):  
Central Nervous System ◽  
Mouse Model ◽  
Amphotericin B ◽  
Fixed Combination ◽  
Central Nervous System Infection ◽  
Naegleria Fowleri ◽  
Combined Use ◽  
Nægleria Fowleri ◽  
Primary Amebic Meningoencephalitis

ABSTRACT Naegleria fowleri is responsible for producing a rapidly fatal central nervous system infection known as primary amebic meningoencephalitis (PAM). To date, amphotericin B, an antifungal agent, is the only agent with established clinical efficacy in the treatment of PAM. However, amphotericin B is not always successful in treating PAM and is associated with severe adverse effects. We previously found azithromycin to be more effective than amphotericin B in a mouse model of PAM. We therefore investigated the combination of amphotericin B and azithromycin in vitro and in a mouse model of PAM. For the in vitro studies, 50% inhibitory concentrations were calculated for each drug alone and for the drugs in fixed combination ratios of 1:1, 3:1, and 1:3. We found amphotericin B and azithromycin to be synergistic at all three of the fixed combination ratios. In our mouse model of PAM, a combination of amphotericin B (2.5 mg/kg of body weight) and azithromycin (25 mg/kg) protected 100% of the mice, whereas amphotericin B alone (2.5 mg/kg) protected only 27% of mice and azithromycin alone (25 mg/kg) protected 40% of mice. This study indicates that amphotericin B and azithromycin are synergistic against the Lee strain of N. fowleri, suggesting that the combined use of these agents may be beneficial in treating PAM.

scholarly journals Activities of Azithromycin and Amphotericin B against Naegleria fowleri In Vitro and in a Mouse Model of Primary Amebic Meningoencephalitis

2003 ◽  
Vol 47 (2) ◽  
pp. 524-528 ◽  
Author(s):  
Shannon M. Goswick ◽  
George M. Brenner
Keyword(s):  
Amphotericin B ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Naegleria Fowleri ◽  
Nægleria Fowleri ◽  
Free Living Ameba ◽  
Primary Amebic Meningoencephalitis ◽  
Observation Period

ABSTRACT Inhalation of fresh water containing the free-living ameba Naegleria fowleri may lead to a potentially fatal infection known as primary amebic meningoencephalitis. Amphotericin B is the only agent with established clinical efficacy in the treatment of primary amebic meningoencephalitis in humans, but therapy with this drug is often associated with adverse effects on the kidneys and other organs, and not all persons treated with amphotericin B have survived. We investigated the in vitro activity and in vivo efficacy of newer therapeutic agents in an attempt to identify other useful agents for treating primary amebic meningoencephalitis. Azithromycin has shown in vitro activity against Acanthamoeba spp. and in vivo activity against experimental toxoplasmosis. In our study, the MIC of azithromycin against N. fowleri was 13.4 μM (10 μg/ml), which was 123 times greater than the MIC of amphotericin B, which was 0.108 μM (0.1 μg/ml). Azithromycin protected 100% of mice infected with N. fowleri at a dose of 75 mg/kg/day for 5 days, whereas amphotericin B protected only 50% of mice at a dose of 7.5 mg/kg/day for 5 days, and all control mice died during the 28-day observation period. We conclude that azithromycin has both in vitro and in vivo activity versus N. fowleri and may be a useful addition to therapy for primary amebic meningoencephalitis.

scholarly journals EdU incorporation to assess cell proliferation and drug susceptibility for the brain-eating amoeba, Naegleria fowleri

2021 ◽  
Author(s):  
Emma V Troth ◽  
Dennis E Kyle
Keyword(s):  
Cell Proliferation ◽  
Drug Discovery ◽  
Quantitative Methods ◽  
Click Reaction ◽  
New Drugs ◽  
Alternative Methods ◽  
Naegleria Fowleri ◽  
Screening Assay ◽  
Nægleria Fowleri

Naegleria fowleri is a pathogenic free-living amoeba that is commonly found in warm, freshwater and can cause a rapidly fulminant disease known as primary amoebic meningoencephalitis (PAM). New drugs are urgently needed to treat PAM, as the fatality rate is >97%. Until recently, few advances have been made in the discovery of new drugs for N. fowleri and one drawback is the lack of validated tools and methods to enhance drug discovery and diagnostics research. In this study we aimed to validate alternative methods to assess cell proliferation that are commonly used for other cell types and develop a novel drug screening assay to evaluate drug efficacy on N. fowleri replication. EdU (5-ethynyl-2´-deoxyuridine) is a pyrimidine analog of thymidine that can be used as a quantitative endpoint for cell proliferation. EdU incorporation is detected via a copper catalyzed click reaction with an Alexa Fluor linked azide. EdU incorporation in replicating N. fowleri was validated using fluorescence microscopy and quantitative methods for assessing EdU incorporation were developed by using an imaging flow cytometer. Currently used PAM therapeutics inhibited N. fowleri replication and EdU incorporation in vitro. EdA (5'ethynyl-2'-deoxyadenosine), an adenine analog, also was incorporated by N. fowleri, but was more cytotoxic than EdU. In summary, EdU incorporation could be used as a complimentary method for drug discovery for these neglected pathogens.

scholarly journals Eight-Year-Old Male With Primary Amebic Meningoencephalitis

2019 ◽  
Vol 6 (8) ◽  
Author(s):  
Chairut Vareechon ◽  
Thomas Tarro ◽  
Claudia Polanco ◽  
Vikram Anand ◽  
Pia S Pannaraj ◽  
...  
Keyword(s):  
Fresh Water ◽  
Clinical Features ◽  
Hot Spring ◽  
Naegleria Fowleri ◽  
Free Living ◽  
Free Living Amoeba ◽  
Nægleria Fowleri ◽  
Primary Amebic Meningoencephalitis

Abstract Naegleria fowleri is a thermophilic free-living amoeba that is found in warm, fresh water and causes primary amebic meningoencephalitis (PAM). The following report demonstrates the rapid and destructive clinical features of PAM in an 8-year-old male who presented with severe headaches approximately 12 days after swimming in a hot spring.

scholarly journals In Vitro Activity of Statins against Naegleria fowleri

Pathogens ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 122 ◽  
Author(s):  
Aitor Rizo-Liendo ◽  
Ines Sifaoui ◽  
María Reyes-Batlle ◽  
Olfa Chiboub ◽  
Rubén L. Rodríguez-Expósito ◽  
...  
Keyword(s):  
Vitro Activity ◽  
In Vitro Activity ◽  
Naegleria Fowleri ◽  
Key Factors ◽  
Key Enzyme ◽  
Liver And Kidney ◽  
Nægleria Fowleri ◽  
Coa Reductase ◽  
Effective Drugs

Naegleria fowleri causes a deadly disease called primary amoebic meningoencephalitis (PAM). Even though PAM is still considered a rare disease, the number of reported cases worldwide has been increasing each year. Among the factors to be considered for this, awareness about this disease, and also global warming, as these amoebae thrive in warm water bodies, seem to be the key factors. Until present, no fully effective drugs have been developed to treat PAM, and the current options are amphotericin B and miltefosine, which present side effects such as liver and kidney toxicity. Statins are able to inhibit the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is a key enzyme for the synthesis of ergosterol of the cell membrane of these amoebae. Therefore, the in vitro activity of a group of statins was tested in this study against two types of strains of Naegleria fowleri. The obtained results showed that fluvastatin was the most effective statin tested in this study and was able to eliminate these amoebae at concentrations of 0.179 ± 0.078 to 1.682 ± 0.775 µM depending on the tested strain of N. fowleri. Therefore, fluvastatin could be a potential novel therapeutic agent against this emerging pathogen.

scholarly journals Evaluation of Indolocarbazoles from Streptomyces sanyensis as a Novel Source of Therapeutic Agents against the Brain-Eating Amoeba Naegleria fowleri

2020 ◽  
Vol 8 (5) ◽  
pp. 789
Author(s):  
Aitor Rizo-Liendo ◽  
Ines Sifaoui ◽  
Luis Cartuche ◽  
Iñigo Arberas-Jiménez ◽  
María Reyes-Batlle ◽  
...  
Keyword(s):  
Therapeutic Agents ◽  
Ros Generation ◽  
Naegleria Fowleri ◽  
Lethal Infection ◽  
The Central Nervous System ◽  
Cell Membrane Disruption ◽  
Nægleria Fowleri ◽  
Opportunistic Pathogenic ◽  
Amoebic Meningoencephalitis ◽  
The Brain

Naegleria fowleri is an opportunistic pathogenic free-living amoeba which is able to rapidly colonize the central nervous system (CNS) and causes a lethal infection known as primary amoebic meningoencephalitis (PAM). Furthermore, more than 98% of the known cases of PAM are fatal and affect mainly children under 12 and young adults. Until now, no fully effective therapeutic agents against N. fowleri are available and hence the urgent need to find novel agents to treat PAM. At present, PAM therapy is based on the combination of amphotericin B, miltefosine, among others, with unwanted toxic effects. Recently, our team isolated various indolocarbazoles (ICZs) from the culture of a mangrove strain of Streptomyces sanyensis which showed activity against kinetoplastids and the Acanthamoeba genus. Hence, in this study, the activity of the previously isolated ICZs, staurosporine (STS), 7-oxostaurosporine (7OSTS), 4′-demethylamino-4′-oxostaurosporine, and streptocarbazole B, was evaluated against two type strains of N. fowleri. Furthermore, the performed activity assays revealed that STS was the most active ICZ presenting an inhibitory concentration 50 (IC50) of 0.08 ± 0.02 µM (SI 109.3). Moreover, STS induced programmed cell death (PCD) in the treated amoebae by triggering DNA condensation, mitochondrial disfunction, cell membrane disruption, and reactive oxygen species (ROS) generation. Therefore, STS could be a promising therapeutic agent against PAM.

scholarly journals Naegleria fowleri: Pathogenesis, Diagnosis, and Treatment Options

2015 ◽  
Vol 59 (11) ◽  
pp. 6677-6681 ◽  
Author(s):  
Eddie Grace ◽  
Scott Asbill ◽  
Kris Virga
Keyword(s):  
Case Reports ◽  
Treatment Options ◽  
Clinical Manifestations ◽  
Naegleria Fowleri ◽  
Content Type ◽  
High Profile ◽  
Free Living Amoeba ◽  
Nægleria Fowleri ◽  
Amoebic Meningoencephalitis

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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