Miltefosine: A Miracle Drug for Meningoencephalitis Caused by Free-Living Amoebas

Alli, Ammar; Ortíz, Juan Fernando; Cox, Álvaro Morillo; Armas, María Guadalupe Guijarro de; Orellana, Victor A

doi:10.7759/cureus.13698

Cited by 9 publications

(8 citation statements)

References 35 publications

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“…Amphotericin B has various side effects such as chills, fever and nephrotoxicity. Miltefosine is another drug that is used synergistically with amphotericin B [ 13 ]. Configurin is an antifungal drug that is FDA approved as an orphan drug for the treatment of N. fowleri infection [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Virtual Screening of Alkaloid and Terpenoid Inhibitors of SMT Expressed in Naegleria sp.

2022

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The pathogenic form of thermophilic Naegleria sp. i.e., Naegleria fowleri, also known as brain eating amoeba, causes primary amoebic encephalitis (PAM) with a >97% fatality rate. To date, there are no specific drugs identified to treat this disease specifically. The present antimicrobial combinatorial chemotherapy is hard on many patients, especially children. Interestingly, Naegleria fowleri has complex lipid biosynthesis pathways like other protists and also has a strong preference to utilize absorbed host lipids for generating energy. The ergosterol biosynthesis pathway provides a unique drug target opportunity, as some of the key enzymes involved in this pathway are absent in humans. Sterol 24-C Methyltransferase (SMT) is one such enzyme that is not found in humans. To select novel inhibitors for this enzyme, alkaloids and terpenoids inhibitors were screened and tested against two isozymes of SMT identified in N. gruberi (non-pathogenic) as well as its homolog found in yeast, i.e., ERG6. Five natural product derived inhibitors i.e., Cyclopamine, Chelerythrine, Berberine, Tanshinone 2A, and Catharanthine have been identified as potential drug candidates based on multiple criteria including binding affinity, ADME scores, absorption, and, most importantly, its ability to cross the blood brain barrier. This study provides multiple leads for future drug exploration against Naegleria fowleri.

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Section: Introductionmentioning

confidence: 99%

Virtual Screening of Alkaloid and Terpenoid Inhibitors of SMT Expressed in Naegleria sp.

2022

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“…It is well known that the progression of PAM is rapid, and over 95% of patients die (12). There are several risk factors related to the outcome of PAM.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have been devoted to new drugs targeting ( 16) fatty acid oxidation, such as etomoxir, orlistat, perhexiline, thioridazine, and valproic acid. Moreover, it is inspiring that miltefosine is considered to decrease the usual mortality rate of both PAM and GAE (12). Another factor related to the outcome is the timing of treatment initiation.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Recognition of Devastating Primary Amoebic Meningoencephalitis (PAM) Caused by Naegleria fowleri: Another Case in South China Detected via Metagenomics Next-Generation Sequencing Combined With Microscopy and a Review

Chen

Che²,

Lin³

et al. 2022

Front. Trop. Dis

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IntroductionPrimary amoebic meningoencephalitis (PAM) caused by Naegleria fowleri is seldom reported in mainland China.MethodsOne case from South China was presented, and the clinical features of the PAM, especially the early CT features, were compared to those in the literatures from PubMed/Web of Science/China National Knowledge internet (CNKI).Case Presentation and ResultsA 47-year-old man with a high fever came to the fever clinic. Twelve hours later, the man lost consciousness and exhibited generalized tonic-clonic seizures and needed ventilator-controlled ventilation. Then, he was admitted to the neurology intensive care unit (NICU). The opening pressure of his cerebrospinal fluid (CSF) was over 500 mm H2O with highly increased leukocyte/protein levels and very low glucose levels. Three days after admission, high copy numbers of Naegleria fowleri amoebae were detected by metagenomics next-generation sequencing (mNGS) and cysts were visible with wet mount microscopy. Four days after admission, the patient experienced brain death. However, the relatives of the patient did not want to give up, and he received amphotericin B (AmB). During hospitalization, he suffered from severe damage to the liver and kidneys and electrolyte disorders that required continuous renal replacement therapy (CRRT).ReviewAll 20 included PAM patients suffered from fever. Seventeen of them had headache and neck stiffness. Ten of them showed generalized brain edema. To date, 7 cases of PAM have been reported in China. Only one patient survived. Most of the patients showed generalized brain edema. Only the surviving patient showed focal edema. He died three months later.ConclusionRapidly progressive meningoencephalitis in which the CSF results are similar to those suffered from a bacterial infection should be considered a possible case of PAM. It can be rapidly detected with microscopy in CSF wet mounts but needs further molecular investigation for confirmation, and mNGS should be a new method used for rapid and precise identification. Moreover, CRRT may prolong the survival time of PAM patients with multiple organ failure.

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“…Miltefosine, an alkylphosphocholine agent, was originally developed as an anticancer drug in the 1980s, but it is now the only FDA-approved antiparasitic medication for the treatment of cutaneous, mucosal, and visceral leishmaniasis [35]. Furthermore, the CDC recommended agent as first-line therapy for infections caused by free-living amoebas [36]. Miltefosine has also shown promising in vitro activity against a variety of clinically significant molds and yeasts, including dimorphic fungi, Aspergillus spp., Candida spp., Cryptococcus spp., Fusarium spp., Rhizopus spp., and Scedosporium spp.…”

Section: Introductionmentioning

confidence: 99%

Potential Inhibitory Effect of Miltefosine against Terbinafine-Resistant Trichophyton indotineae

et al. 2023

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Several prolonged and significant outbreaks of dermatophytosis caused by Trichophyton indotineae, a new emerging terbinafine-resistant species, have been ongoing in India in recent years, and have since spread to various countries outside Asia. Miltefosine, an alkylphosphocholine, is the most recently approved drug for the treatment of both visceral and cutaneous leishmaniasis. Miltefosine in vitro activity against terbinafine-resistant and susceptible T. mentagrophytes/T. interdigitale species complex, including T. indotineae, is limited. The current study aimed to assess miltefosine’s in vitro activity against dermatophyte isolates, which are the most common causes of dermatophytosis. Miltefosine, terbinafine, butenafine, tolnaftate, and itraconazole susceptibility testing was performed using Clinical and Laboratory Standards Institute broth microdilution methods (CLSI M38-A3) against 40 terbinafine-resistant T. indotineae isolates and 40 terbinafine-susceptible T. mentagrophytes/T. interdigitale species complex isolates. Miltefosine had MIC ranges of 0.063–0.5 µg/mL and 0.125–0.25 µg/mL against both terbinafine-resistant and susceptible isolates. In terbinafine-resistant isolates, the MIC50 and MIC90 were 0.125 µg/mL and 0.25 µg/mL, respectively, and 0.25 µg/mL in susceptible isolates. Miltefosine had statistically significant differences in MIC results when compared to other antifungal agents (p-value 0.05) in terbinafine-resistant strains. Accordingly, the findings suggest that miltefosine has a potential activity for treating infections caused by terbinafine-resistant T. indotineae. However, further studies are needed to determine how well this in vitro activity translates into in vivo efficacy.

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Miltefosine: A Miracle Drug for Meningoencephalitis Caused by Free-Living Amoebas

Cited by 9 publications

References 35 publications

Virtual Screening of Alkaloid and Terpenoid Inhibitors of SMT Expressed in Naegleria sp.

Virtual Screening of Alkaloid and Terpenoid Inhibitors of SMT Expressed in Naegleria sp.

Case Report: Recognition of Devastating Primary Amoebic Meningoencephalitis (PAM) Caused by Naegleria fowleri: Another Case in South China Detected via Metagenomics Next-Generation Sequencing Combined With Microscopy and a Review

Potential Inhibitory Effect of Miltefosine against Terbinafine-Resistant Trichophyton indotineae

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