Authors: Aditya Tyagi, Rushdanya Bushra, and Deniz Tiryakioglu
Abstract:
Known as the "brain-eating amoeba," Naegleria fowleri is a thermophilic, free-living protozoan that causes primary amoebic meningoencephalitis (PAM), an infection of the central nervous system that is uncommon but nearly always fatal. This review looks at the pathophysiology, difficulties with diagnosis, and approaches to treating infections caused by N. fowleri. The pathogenesis starts when the amoeba's trophozoite form enters the nasal passages, usually as a result of exposure to freshwater. It then migrates down the olfactory nerve and infiltrates the brain, resulting in extensive and fast neuroinflammation as well as necrosis. The early symptoms of PAM are nonspecific and mirror bacterial meningitis, making clinical identification difficult and raising suspicion in endemic locations. Cerebrospinal fluid (CSF) examination is necessary for diagnostic confirmation; the presence of motile trophozoites or positive PCR results indicate infection. There are few and frequently ineffective treatment options available; however, a combination therapy using amphotericin B, rifampin, and miltefosine has demonstrated some success. Aggressive treatment and early diagnosis are still essential for patient survival. In order to tackle this fatal infection, this systematic review emphasizes the need for increased awareness, quick diagnosis methods, and innovative therapy options.
Diagnosis:
The primary methods for diagnosing Naegleria fowleri are imaging scans, laboratory testing, and clinical suspicion. A lumbar puncture is usually done to acquire cerebrospinal fluid (CSF) for investigation when PAM is suspected. Low glucose, high protein levels, and an increased white blood cell count (pleocytosis) are common findings in the CSF of patients infected with Naegleria fowleri. These findings are also suggestive of bacterial meningitis. However, to identify the amoeba itself, particular diagnostic procedures are required.
Detection of Naegleria fowleri in Patients:
Several laboratory methods can be used to identify Naegleria fowleri in patients. Motile amoebae can be directly detected by direct microscopic analysis of the CSF under a microscope, although this technique needs a trained technician and is not always conclusive. A variety of staining methods, including trichrome or Giemsa-Wright, can improve the amoebae's appearance in CSF samples.
Polymerase chain reaction (PCR) and immunofluorescence assays are examples of more sophisticated techniques. Naegleria fowleri DNA can be found in CSF samples using PCR, a very sensitive method that offers a conclusive diagnosis. Through the use of fluorescent
dye-tagged antibodies that bind to Naegleria fowleri specifically, immunofluorescence assays enable the detection of the organism under a fluorescence microscope. Even though these techniques are more precise, not all healthcare facilities may be able to use them because they need certain tools and skilled workers.
Imaging tests like magnetic resonance imaging (MRI) and computed tomography (CT) scans can aid in the diagnosis in addition to CSF analysis by identifying brain abnormalities that are consistent with PAM. These could include enlargement of the brain and other indicators of severe inflammation. Initiating proper treatment for Naegleria fowleri requires early and precise detection. This treatment may involve a combination of antimicrobial medicines and supportive care measures. The prognosis for PAM is still poor despite these efforts, which emphasizes the significance of prompt identification and treatment.
Treatment:
Due to the rarity of human infections, case reports and in vitro research mostly inform treatment choices for N. fowleri infections. Based on this research, amphotericin B is generally regarded as the most effective medicine, despite the paucity of clinical trials evaluating therapeutic efficacy. Furthermore, case reports have included the use of additional anti-infectives, though their effectiveness may vary, such as azithromycin, rifampin, miltefosine, miconazole, and fluconazole. Other agents, such as hygromycin, roxithromycin, clarithromycin, erythromycin, roxithromycin, and zeocin, have also been examined in vitro and/or in vivo. Nevertheless, more research is needed to fully understand their clinical usefulness and effectiveness in treating N. fowleri infections.
Amphotericin B
In a recent study, a total of 381 global cases of PAM were identified from 1937 through 2018, and only seven survivors were reported. (Debnath 2)
From 1937 to 2013, there were 142 reported cases of PAM in the United States. Treatment data for 70 of the 142 (49%) patients were available. Among these patients, 36 (51%) received treatment for PAM, and 3 (8%) of them survived. All 36 patients treated for PAM were administered amphotericin B, with 7 (19%) receiving only intravenous (IV) therapy, 5 (14%) receiving only intrathecal (IT) therapy, and 24 (67%) receiving a combination of IV and IT therapy. Additionally, 7 patients received a non-deoxycholate amphotericin B formulation, which includes liposomal and lipid complex formulations.
The original US survivor and the 2013 survivors received deoxycholate amphotericin B. AmBisome, the liposomal formulation of amphotericin B, was approved for use in the United States in 1997 by the US Food and Drug Administration. Patients treated with amphotericin B for Naegleria after 1997 were more likely to receive the liposomal preparation, as fewer renal adverse effects have been reported with this formulation. However, it has been found that liposomal amphotericin B is less effective against N. fowleri in vitro and in a mouse model compared to deoxycholate amphotericin B.
It's important to note that these findings came from two different studies, and the deoxycholate formulation was given at a higher dose than what is typically used in patients.
Seven patients with N. fowleri infection received a non-deoxycholate formulation. Given the extremely poor prognosis of PAM caused by N. fowleri, healthcare providers might want to consider using deoxycholate amphotericin B instead of the liposomal or lipid complex formulation. However, if deoxycholate amphotericin B is not immediately available, treatment should be initiated with a non-deoxycholate formulation to facilitate prompt treatment of the patient.
Treatment history of seven confirmed survivors showed that all survivors received amphotericin B, either intravenously or both intravenously and intrathecally. Only one survivor received amphotericin B alone; the rest of the survivors were treated with a combination of drugs. (Debnath 2)
Unfortunately, amphotericin B alone is not universally effective. It was administered to nearly three-quarters (71%) of PAM patients. The formulation of amphotericin B (e.g., deoxycholate vs. lipid or liposomal) may play a role in treatment effectiveness. Conventional deoxycholate formulations have shown greater efficacy in vitro and in mouse models, despite greater adverse effects. Additionally, amphotericin B and the other drugs included in survivors’ regimens may not be available in all settings. Multiple case reports specifically mentioned unavailability of amphotericin B at the time of patient presentation and diagnosis.(Gharpure et al. 7)
The repurposing of antifungal drugs in the drug discovery of Primary Amebic Meningoencephalitis (PAM) has a historical context. Amphotericin B, an antifungal drug, was used in all confirmed survivors and administered to about three-quarters of PAM patients.
However, it was not universally effective. (Debnath 5)As a result, researchers investigated the effect of other antifungal drugs to identify a more active and less toxic alternative to amphotericin B.
A water-soluble polyene macrolide called corifungin, which is in the same class as amphotericin B, was tested against N. fowleri trophozoites. The compound was found to be twice as potent as amphotericin B. Although in vitro studies suggested that corifungin may have a similar mechanism of action to amphotericin B in N. fowleri, the increased solubility of corifungin may have contributed to its better tolerability and pharmacokinetic distribution in animals. (Debnath 4)
Silver nanoparticles were conjugated with amphotericin B, resulting in enhanced amebicidal activity. Additional studies are needed to confirm whether this increased activity observed in vitro translates to improved drug delivery and efficacy in animal models. (Debnath 4)
Miltefosine
In 1980, the drug miltefosine was first used as an experimental treatment for breast cancer. It has been observed that the Naegleria parasite can cause a strong inflammatory response, resulting in tissue damage and bleeding. By 2013, the CDC had reported 26 cases where miltefosine was used.
In a laboratory study, miltefosine was compared with amphotericin B over the course of a month. The study found that the minimum amount of the drug needed to inhibit the growth of the parasite was 0.25 ug/ml for miltefosine and 0.78 ug/ml for amphotericin B. The survival rates for patients treated with miltefosine were 55%, compared to 40% for those treated with amphotericin B. The optimal dosage, frequency, and treatment duration for miltefosine are not yet fully understood, but a common recommendation is to not exceed 50 mg tablets and a maximum daily dosage of 2.5 mg/kg. The duration of treatment varies depending on the individual case.
In 2013, two children survived and recovered from primary amoebic meningoencephalitis after being treated with miltefosine. In 2016, another child became the fourth person in the United States to survive Naegleria fowleri infection after receiving treatment that included miltefosine.
In 2013, during the summer, a 12-year-old girl from Arkansas was successfully treated with a drug called Miltefisine for PAM, leading to full neurological recovery. The treatment also involved the administration of MLT, AmB, FCZ, AZM, RIF, and Dexamethasone (DEX). In addition, the girl was put into a hypothermic state to manage intracranial pressure and reduce brain injury caused by hyperinflammation.
The treatment regimen used in a 12-year-old girl was later administered to two other patients, a 12-year-old boy and an 8-year-old boy. One of them survived but experienced poor neurological function, including static encephalopathy, profound mental disability, and partial seizure disorder control with anticonvulsant therapy. The other patient unfortunately did not survive and was declared brain-dead on hospital day 16 due to brain herniation.
Her treatment plan included all the medications administered to the two patients. Notable distinctions in her medical progress and treatment compared to the two patients mentioned here involved receiving Naegleria-specific drugs about 48 hours after symptoms appeared and undergoing intensive management of increased pressure inside the skull, which included therapeutic hypothermia.
The three patients discussed in this report all received miltefosine as part of their treatment for Naegleria infection, but their outcomes varied widely. One patient died, another survived with significant neurological impairment, and the third survived with full neurological recovery. This shows that while miltefosine shows promise as a treatment for Naegleria infection, it is not a guaranteed cure. Since 2013, all surviving US patients with Naegleria infection received miltefosine, compared to only a third of fatal cases. Successful treatment of Naegleria infection likely involves early diagnosis, combination drug therapy (including miltefosine), and aggressive management of elevated intracranial pressure, similar to the approach used in treating traumatic brain injury.
Azithromycin
Although amphotericin B is the first choice for treating primary amebic meningoencephalitis, it is often associated with renal toxicity, leading to azotemia and hypokalemia. Furthermore, not all patients treated with amphotericin B have survived primary amebic meningoencephalitis.
In a study, researchers found that azithromycin, a macrolide antibiotic, was chosen for the study based on previous reports describing the in vitro sensitivity of Acanthamoeba spp. to this drug and its activity in experimental toxoplasmosis. The researchers discovered that azithromycin was highly active against N. fowleri in vitro and that it protected 100% of mice infected with N. fowleri at a dose of 75mg/kg of body weight per day for 5 days. In contrast, amphotericin B only protected 50% of mice at a dose of 7.5 mg/kg per day, while all control mice died during the 28-day observation period. As azithromycin is a relatively non-toxic agent that might be useful in treating PAM alone or in combination with amphotericin B, the researchers evaluated the combined activity of azithromycin and amphotericin B in vitro and in vivo.
In this study, it was discovered that the combination of amphotericin B and azithromycin had a synergistic effect against N. fowleri when used together in fixed concentration ratios of 1:1, 1:3, and 3:1. The study also investigated the combined effect of these two drugs in a mouse model of PAM. It was found that a combination of 2.5 mg/kg of amphotericin B and 25 mg/kg of azithromycin, administered once daily for 5 days, provided 100% protection to mice infected with N. fowleri. In comparison, when used individually, amphotericin B and azithromycin only protected 27% and 40% of mice, respectively. These findings suggest that the combined use of these agents was 100% effective, while each agent alone was less than 50% effective, consistent with the observed synergy in vitro.
There is little known about the mechanism of action of azithromycin against N. fowleri. Azithromycin inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit and blocking peptide bond formation and translocation. Azithromycin has been shown to be widely distributed in brain tissue following systemic administration in humans, whereas amphotericin B exhibits poor penetration of the blood-brain barrier. N. fowleri exposed to amphotericin B rounds up and fails to form pseudopodia. The ultrastructural abnormalities included alteration of nuclear shape, degeneration of mitochondria, and the appearance of autophagic vacuoles.
The current study shows that azithromycin and amphotericin B have a synergistic effect against the Lee strain of N. fowleri. This suggests that using these two agents together could be an effective treatment for human infections with this organism. Further research should be done to determine the exact range of synergistic activity of these two agents, and additional studies with other agents could be conducted to improve the selection of drugs and the treatment of N. fowleri infection.
Rifampin
Although rifampin has been used in all of the PAM survivor cases in the United States and Mexico (all three cases in the United States and one survivor in Mexico), its efficacy remains questionable.
The main issue is whether enough rifampin enters the central nervous system (CNS) at standard therapeutic doses. Several studies have shown that rifampin reaches favorable concentrations in the CNS, as measured by drug concentrations in the cerebrospinal fluid (CSF). However, a report by Mindermann et al. found significant variations in the concentrations of rifampin in different parts of the CNS. Concentrations in the cerebral extracellular space and in normal brain tissue were measured at 0.32 ± 0.11 μg/ml and 0.29 ± 0.15 μg/ml, respectively. These concentrations would be sufficient to exceed the required minimum inhibitory concentration (MIC) for most susceptible bacteria but might not be enough to eradicate N. fowleri.
In an initial report by Thong et al. in 1977, it was found that the natural product rifamycin delayed the growth of N. fowleri by 30 to 35% when used at concentrations of 10 μg/ml over a 3-day period. However, rifamycin lost its ability to inhibit N. fowleri growth by the 6th day of incubation. It was observed that growth inhibition (>80%) was sustained for the entire 6-day period only when higher concentrations of rifampin, a semisynthetic analogue of rifamycin (100 μg/ml), were used.
The later report by Ondarza did not show any minimum inhibitory concentration (MIC) for rifampin against N. fowleri. It revealed a 50% inhibitory concentration (IC50) of >32 μg/ml, which was the highest concentration tested in the study. These findings do not provide evidence to support the use of standard doses of rifampin for treating PAM.
One issue with using rifampin to treat N. fowleri is the high potential for drug-drug interactions when combined with other medications. Rifampin is known to induce the CYP2 and CYP3 family of monooxygenase enzymes, specifically CYP2C9, CYP2C19, and CYP3A4. The greatest likelihood for interaction with rifampin is when it is used with 14α-demethylase inhibitors, also known as the azole fungistatics.
In most cases, miconazole was initially used before switching to fluconazole in more recent cases. 14α-Demethylase is a specific isoform, and there are known interactions between rifampin and fluconazole. When these two drugs are taken together, it leads to significant changes in the way fluconazole is processed in the body: a decrease of more than 20% in the area under the concentration-time curve (AUC), up to a 50% decrease in critically ill patients, at least a 30% increase in clearance rate, and a 28% shorter half-life. Since there has been a demonstrated synergy between 14α-demethylase inhibitors and amphotericin B against N.fowleri, adding rifampin to the combination may not be very beneficial and could actually work against the maximum therapeutic effect of the other agents.
Fluconazole
In certain instances of Naegleria fowleri infection, amphotericin B has been used with the azole antifungal medication fluconazole for therapy. Studies show that some patients benefit further from fluconazole added to amphotericin B medication.Fluconazole may be more effective than amphotericin B because it reaches the central nervous system (CNS) more profoundly.
Fluconazole and amphotericin B have synergistic actions that help to eradicate N. fowleri infection, presumably as a result of neutrophil recruitment. As a result, fluconazole can be used as an addition to amphotericin B in individuals suspected of having N. fowleri.The CDC advises administering intravenous fluconazole once day at a dose of 10 mg/kg/day, up to a maximum of 600 mg/day, for a total of 28 days. The goal of this dosage schedule is to maximize fluconazole's therapeutic efficacy in N. fowleri infections.Another azole antifungal that works well against N. fowleri in vitro is voriconazole, which is effective at doses of at least 1 μg/ml.
Specifically, fluconazole has been combined with additional medications, including rifampin, miltefosine, and amphotericin B, to develop a multimodal therapy plan. In addition to fluconazole's inhibition of ergosterol synthesis, amphotericin B works by binding to ergosterol and creating holes in the cell membrane. The medicine miltefosine, which was first created as an anti-leishmanial medication, has demonstrated amoebicidal activity, which increases the efficacy of the treatment plan.
Clinical instances have shown that combined therapy can provide better results than monotherapy, but because PAM progresses aggressively and is difficult to diagnose in a timely manner, survival rates are still low. A further difficulty is the blood-brain barrier, which restricts the amount of medication that can reach the infection site. To enhance azoles' and other therapeutic agents' penetration of the central nervous system, research is still being done on dose regimens and drug delivery techniques.
Despite these challenges, azoles remain a crucial component in the therapeutic arsenal against brain-eating amoebas. Ongoing research and clinical trials are essential to refine treatment protocols and enhance the efficacy of these drugs, offering hope for improved survival rates in affected patients. Early diagnosis and prompt initiation of combination therapy are vital, emphasizing the need for heightened awareness and rapid medical response to symptoms indicative of PAM.
Vaccination as a Potential Treatment Strategy:
Vaccines play a crucial role in the treatment strategies for all diseases, including infections caused by Naegleria fowleri. However, despite recent efforts, a universally accepted and officially authorized vaccination for Naegleria fowleri remains undiscovered. This section will address and discuss potential candidate proteins for an innovative method of treating this lethal infection.
In a recent study, Gutiérrez-Sánchez et al. (2023) investigated the role of two potential antigen vaccine candidates, a 19 kDA polypeptide and a MP2CL5 peptide, using a BALB/c mouse model (Gutiérrez-Sánchez, 2023). They measured the immunologic response using different methods; including flow cytometry, ELISA, and the investigation of specific antibodies (IgA, IgG, and IgM) in the serum and nasal cavity. According to the results, the use of 19-kDa polypeptide yielded promising results, with a 80% protection rate against Naegleria fowleri infection. In addition, when combined with cholera toxin (CT), this vaccine candidate demonstrated up to 100% protection. Although both antigens showed a specific immune response against infection, a noteworthy increase in the number of T and B lymphocytes was observed by the team in nasal passages and nasal-associated lymphoid tissue. Finally, increased levels of IgA, IgG, and IgM in vaccinated mice were detected, both in the serum and nasal cavity. These findings highlight the potential of these antigens as a promising candidate for a vaccine against Naegleria fowleri infections due to their high efficacy and capacity to offer localized protection.
Another separate study was conducted to assess the immunological effects of an mRNA-based vaccination for the treatment of PAM by Naveed and his team using a BALB/c mouse model (Naveed, Muhammad, et al., 2024). They analyzed the responses by measuring T-cell numbers and using IgA and IgG antibody levels in various samples, including mucosal tissue and serum. In this study, increased antibody levels were detected in both samples, suggesting a systemic response against Naegleria fowleri antigens. Moreover, the production of important cytokines such as IFN-γ were also observed. This highlights the enhanced T-cell responses in the mice model. This holds significance since it implies a strong immune response. The group also stated no side or adverse effects on the model during or after the trials, impling its safety.
Despite the promising results, more clinical and preclinical trials are needed to decide whether mRNA vaccines hold a potential to treat PAM in patients (Naveed, Muhammad, et al., 2024).
Immunoinformatics is another popular technique used by many researchers to develop vaccines in a safer way. In 2023, Sarfraz et al. demonstrated the use of this innovative method to develop a preventative approach for PAM infections. The objective of this study was to find distinct T- and B-cell epitopes through the utilization of diverse screening techniques. Different parameters including cytokine-inductivity, allergenicity, toxicity, antigenicity were taken into account to find epitopes that trigger the immune responses of both cell types (Sarfraz, Asifa, et al., 2023).
Although further research and the support of more clinical studies are needed to fully demonstrate its efficacy on patients suffering from PAM infections, a multi-epitope vaccine from the most-identified epitopes of B- and T-cells was constructed as a result of this study. This emphasizes the importance of employing computational techniques in vaccine design, utilizing a fast and efficient method (Sarfraz, Asifa, et al., 2023).
Vaccines are a crucial component of therapy strategies. Although there is a dearth of research on vaccine development for Naegleria fowleri infections, multiple studies have consistently shown encouraging and thus promising outcomes. This serves as a reminder that conducting additional study can lead to the identification of more antibodies, which can be advantageous in the treatment of this lethal disease.
Conclusion:
Naegleria fowleri, often referred to as the "brain-eating amoeba," remains a formidable pathogen due to its rapid pathogenesis and the high fatality rate associated with primary amoebic meningoencephalitis (PAM). This review highlights the critical challenges in diagnosing and treating infections caused by N. fowleri, emphasizing the need for heightened awareness and advanced diagnostic methods to facilitate early detection. The pathogenesis involves the amoeba entering the nasal passages and migrating to the brain, causing extensive neuroinflammation and necrosis. The diagnostic process is complicated by the nonspecific early symptoms of PAM, which mimic bacterial meningitis, necessitating specific cerebrospinal fluid (CSF) examination and advanced laboratory techniques like PCR and immunofluorescence assays.
Treatment strategies, though limited, have shown some promise. Amphotericin B remains the cornerstone of therapy, though its efficacy varies, and it is often accompanied by significant adverse effects. Combination therapies, including miltefosine, azithromycin, rifampin, and fluconazole, have shown synergistic effects and improved outcomes in some cases, but these treatments are not universally effective and are often hindered by issues such as drug availability and the ability to penetrate the blood-brain barrier.
Moreover, the exploration of innovative treatment strategies, such as vaccine development, presents a promising frontier in combating N. fowleri infections. Studies investigating potential vaccine candidates, such as the 19 kDa polypeptide, MP2CL5 peptide, and mRNA-based vaccines, have shown encouraging results in animal models, highlighting their potential to offer localized and systemic protection against N. fowleri. Immunoinformatics approaches further underscore the potential for developing multi-epitope vaccines, utilizing computational techniques to identify effective T- and B-cell epitopes.
In conclusion, while significant progress has been made in understanding the pathogenesis, diagnosis, and treatment of N. fowleri infections, challenges remain. Early and precise diagnosis, aggressive and combination treatment strategies, and innovative approaches like vaccine development are essential to improving patient outcomes. Continued research and clinical trials are crucial to refining these strategies and enhancing the efficacy of treatments, offering hope for better survival rates in the face of this lethal infection.
References
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Author Biographies
Aditya Tyagi, a rising junior, is passionately pursuing a career as a neurosurgeon. With a deep interest in the medical field, Aditya aims to impact people's lives positively through science and research. His commitment to understanding the human body and finding innovative medical solutions drives his dedication to becoming a neurosurgeon. Aditya is determined to make a meaningful difference in patients' lives through his future work in medicine. Rushdanya Bushra is currently a student at Govt. Hazi Muhammad Mohsin College. From a very young age, Rushdanya has had a keen interest in biology. Rushdanya always longed to delve deeply into this subject, and over time, his interest developed into a habit. He never get bored reading anything related to this field. His interest deepened when Rushdanya began looking through his aunt’s medical books and research works, sparking his own desire to pursue this type of research. Now Rushdanya wants to pursue my higher education in a biology-related subject so that he can engage with his passion. Rushdanya wants to gain a deeper understanding of the mechanisms of living organisms and learn about diseases and their treatments.
Deniz is a passionate 17-year-old high school student from Turkey with a dream of becoming a neurologist specializing in neurodegenerative diseases, particularly Parkinson’s. She spends her free time reading books and playing volleyball. Inspired by a fascination with the complexities of the brain, she is dedicated to understanding and someday treating Parkinson’s disease. Her academic pursuits are driven by a desire to contribute meaningfully to neuroscience, aiming to make a difference in the lives of those affected by neurological conditions.