Potential Application of Vaporized Drugs via Nasal Inhalers to Prevent Mortality and Central Nervous System Damage Caused by Primary Amoebic Meningoencephalitis Due to Naegleria fowleri

Abstract

Here, it is proposed that nasal inhalers with specific anti-Naegleria fowleri drugs or a combination of anti-N. fowleri compounds combined with steroids such as dexamethasone could provide a practical solution for treating primary amoebic meningoencephalitis.

Primary amoebic meningoencephalitis (PAM) due to the protozoan pathogen Naegleria fowleri is a fulminant infection of the brain that results in death within days.¹ Nasal exposure to contaminated water during swimming, ablution, nasal irrigation, bathing, etc. is the key factor in contracting PAM.¹ During exposure to contaminated water, the parasite attaches itself to the nasal epithelium and then migrates along the olfactory neuroepithelial route to reach the porous cribriform plate and invades the central nervous system, resulting in PAM.¹ First reported in 1965 by Fowler and Carter,² the mortality rate of PAM has remained over 95%, in spite of advances in antimicrobial chemotherapy and supportive care.¹N. fowleri exhibits three stages in its life cycle, including a dormant cyst stage, a flagellate stage, and an active amoeboid stage. In biopsies and necropsies, N. fowleri is always found in the amoeboid form. The amoeboid form contains typical eukaryotic organelles enclosed in a plasma membrane made of ergosterol, thus offering several targets for therapeutic interventions. In this regard, a plethora of compounds have been identified that are highly potent in affecting N. fowleri viability in vitro, but their efficacy in vivo remains questionable. Worryingly, even with accurate diagnosis, the prognosis is extremely poor, and PAM often results in death of the patient. In part, this might be due to our inability to achieve minimum inhibitory concentration at the site of infection, i.e., the brain. Despite such high failure in achieving successful prognosis over the past 55 years, it is puzzling that the mode of treatment has often remained the same, i.e., intravenous application of drugs. This mode of treatment requires large dose of drugs such as amphotericin B (5–10 mg/kg/day) to achieve the minimum inhibitory concentration at the epicenter of the infection, i.e., the brain. The presence of a highly selective blood–brain barrier (BBB) hinders drug transport to the brain to exact its effects. Furthermore, due to venous drainage, the drug dosage at a higher concentration leads to unwanted side effects such as hepatotoxicity, nephrotoxicity, etc. Given that N. fowleri enters the nose and follows the olfactory neuroepithelial route to enter the CNS, it is proposed that the drug application should be done via the intranasal route. Given the acute nature of PAM and the fact that anti-N. fowleri therapeutics do not easily cross the BBB to counteract neuropathologies, it is logical to modulate drugs to target the brain intranasally. The addition of intranasally administered drugs to the current treatment regimen for PAM due to N. fowleri has the potential to improve efficacy, reducing damage to the brain as well as mortality. The proposed route of drug delivery utilizes the glymphatic system that is associated with the trigeminal and olfactory pathways that has been exploited for therapeutic applications in the delivery of molecules to the CNS.³ In support, recent studies have suggested the glymphatic system as an important route to rapidly deliver imine groups of molecules to the brain. Using this system, intranasal imines reached the cortex and other brain regions readily. Given the delivery to the brain is noninvasive, the administration of drugs intranasally is advantageous to existing intravenous applications with minimal damage to other tissue due to systemic administration. This mode of drug delivery can be preferable, and repeated applications are usually well-tolerated and act to escalate drug delivery to the brain.³ The intranasal route for drug delivery combined with vaporized forms of anti-N. fowleri compounds can be efficient in using the glymphatic system to reach the brain, bypassing the BBB. By avoiding the hematogenous route, the proposed intranasal route can be effective in achieving minimum inhibitory concentration at a lower concentration at the site of infection.

Notably, vaporized drugs have been shown to be more effective than the liquid form.⁴ For example, minimum inhibitory concentration of antifungal properties of Cymbopogon citratus in the vapor phase were significantly higher (32.7 mg/L) compared with the liquid phase (288 mg/L), resulting in 100% cidal effects against Candida albicans. It was suggested that the presence of these antimicrobial agents in the gaseous form facilitated their solubilization in cell membranes, resulting in higher cellular damage as observed with surface deformities/ruptured cells, albeit the precise underlying molecular mechanisms of enhanced efficacy of drugs in gaseous form are incompletely understood. The intranasal drug delivery using vaporized anti-N. fowleri is advantageous over intrathecal and/or intraventricular administration of drugs that involve surgical procedures with serious associated complications.

Intranasal drug delivery is an existing mode of delivery that has been used for delivering pharmaceutical compounds for treatment of different health issues such as sinus-related, migraines, bone loss and breaks, and hormonal management of endometriosis. Different factors could affect the delivery of such compounds nasally, such as molecular size (especially with 1000g/mol), physiochemical properties, and hydrophobicity and surface charge. There are different approaches that could be adopted to increase the adsorption.⁵ The anti-N. fowleri drugs suggested here have a molecular weight that ranges from 219–947 g/mol, and the drugs currently used in the market for curing different health issues have molecular weight ranging from 280–3432 g/mol, therefore suggesting that the proposed drugs offer promise in delivering drugs intranasally using nasal sprays (Table 1 and Figure 1).

Table 1. Chemical and Physical Properties of Selected Compounds.

Figure 1.

Currently used anti-Naegleria fowleri compounds for possible inclusion in nasal sprays (white bars). Compounds that are presently used in nasal sprays for non-PAM conditions are also shown in black bars.

It is paramount that future clinical research should investigate vaporized anti-N. fowleri drugs intranasally in addition to the intravenous route for the treatment of PAM due to N. fowleri. Once the efficacy of vaporized drug administration via the intranasal route is proven against PAM due to N. fowleri, then it could complement or replace the intravenous route for relieving neurological complications. Using vaporized anti-N. fowleri drugs intranasally, treatment could be given at regular intervals to prevent brain damage. Nasal inhalers with specific anti-N. fowleri drugs or a combination of anti-N. fowleri compounds plus steroids such as dexamethasone to target pathogenic amoebae as well as reducing increased intracranial pressure could provide a practical solution for treating PAM. To develop the application, it is important to determine an appropriate exposure time for achieving 100% killing. The simplicity of nasal application and the rapid delivery of vaporized anti-N. fowleri drugs to the brain makes this method especially beneficial for easy administration, even in a primary healthcare setting. In addition, self-administration can be carried out, where access to a tertiary hospital may not be possible or is delayed. Furthermore, nasal administration could also be used both as a prophylactic and in postexposure situations, making it an appropriate option in designing preventative and/or therapeutic strategies against PAM.

Author Contributions

^# R.S. and M.Y.A. contributed equally to this manuscript. R.S. and N.A.K. conceptualized the work amid critical discussions with M.K. and T.I. M.Y.A. and R.S. conducted literature review, analysis, and prepared the first draft of the manuscript and the figures under the supervision of N.A.K. All authors contributed to the manuscript and will act as guarantors.

The authors declare no competing financial interest.