Abstract
We propose the use of novel adsorbents, namely, micelle–clay complexes, made up of cetyl-pyridinium chloride (CPC) and clay for the eradication of keratitis-causing Acanthamoeba. The possibility of adding CPC, approved by the FDA for human use, in a contact lens disinfectant to formulate effective disinfectants is discussed further.
Dear Editor,
Acanthamoeba keratitis is a very painful, sight-threatening infection, which is often associated with the improper use of contact lenses.1–3 The morbidity rate associated with Acanthamoeba keratitis has remained significant despite our advances in the antimicrobial chemotherapy and supportive care. For example, Ting et al.4 showed recently that the incidence rate of infectious keratitis was 34.7 per 100,000 people per year, on the order of bacterial, amoebal, and fungal keratitis. It was further suggested that microbial keratitis remains a substantial problem in the UK, and the incidence rate of Acanthamoeba keratitis is likely underreported; this is of particular concern in the developing countries where the use of contact lenses for cosmetics purpose is on the rise.4 In part, this is due to our incomplete understanding of the pathogenetic mechanisms of the disease, inefficacy of contact lens disinfectants, improper handling of the contact lenses, sleeping or swimming while wearing contact lenses, ineffective treatment regimen, and the emergence of drug-resistant amebae strains and similarity with other keratitis-causing pathogens. For example, Acanthamoeba keratitis is often misdiagnosed as bacterial keratitis leading to delayed diagnosis. Treatment for Acanthamoeba keratitis is costly and laborious, which involves topical application of a mixture of drugs every hour of the day and night for few days, followed by application every few hours.3 Treatment can last for months and even then recurrence can occur, in which case corneal transplant is performed as the last resort.1–3
Recently, Bagga et al.5 compared the clinical effectiveness of topical voriconazole (1%) versus the combination therapy of polyhexamethylene biguanide (0.02%) plus chlorhexidine (0.02%) in the treatment of Acanthamoeba keratitis. The results revealed that the efficacy of topical application of voriconazole as a monotherapy was analogous to the combination therapy of polyhexamethylene biguanide plus chlorhexidine.5 In addition to antiamoebic agents, the treatment regimen involves antibiotics and possibly steroids. Such aggressive and intense treatment regimen presents social and economic burden. Hence, an effective preventative strategy remains the most feasible option. Advances have been made in the development of contact lens disinfectants that have proven effective against bacterial pathogens and frequently against Acanthamoeba trophozoites, but effective eradication of the cyst form of amebae remains a challenge.1,2 Cyst is a dormant form with minimal and/or no metabolic activity.1 The majority of active antimicrobial agents are designed against the functional aspect of an organism such as synthesis of proteins, RNA, DNA, cell wall, metabolism, etc.; however, they are not effective against the cyst form as it exhibits limited functional activity. It is easier to destroy “a function” than “a structure.” How can you kill cyst that is acting as “dead” and exhibiting limited functional activity?1
The present disinfection strategy is the chemical removal of amebae (and bacteria) with chlorohexidine as one of the most common disinfectant; however, their effectiveness is questionable especially against the hardy cyst stage. Hydrogen peroxide-based disinfectants are highly effective6; however, its stability is a concern and may present adverse effects, due to its carcinogenic property such as damage to the DNA by releasing free radicals.1,2 Hence, it is used in very minute concentrations. When it comes to killing microbial pathogens such as Acanthamoeba, several agents are shown to be effective, but the concentration at which they are used may not be physiologically relevant, and it is a major cause for concern.2 In addition to safety concerns, the rise of antimicrobial resistance in amebae highlights the need to develop novel contact lens disinfectant ingredients. Ideally, a disinfection strategy that relies on a single ingredient is preferable, rather than many agents in lower concentrations.
Cetyl-pyridinium chloride (CPC) is often seen as a potent broad spectrum cationic quaternary ammonium salt with antibacterial properties.7 It is widely used for oral hygiene and included in mouthwashes/toothpastes and approved by the FDA for human consumption. It is shown to be effective against bacterial pathogens and inhibiting plaque formation.8 For example, an agent called C31G, a mixture of alkyl dimethyl glycine and alkyl dimethyl amine oxide, was found to be more effective than chlorohexidine in both action and adverse effect against bacterial pathogens.7
In addition, natural clays have been used traditionally as folk medicine in the treatment of skin infections and are well known to possess antibacterial properties. Given the increasing emergence of drug-resistant microbes, there has been renewed interest in the use of clay as antimicrobial agents.9 Clay denotes minerals of less than 2 μm in size and commonly includes minerals such as smectite, illite, and kaolinite. When hydrated, minerals dissolve and oxidize, and during this process, metals are released such as Fe and Al, leading to oxidative stress and membrane damage, respectively.10 It is likely that clay exhibits similar properties against Acanthamoeba. Given the antibacterial properties of CPC and clay, another novel method to disinfect contact lenses could involve the use of micelle–clay complexes. Instead of trying to eliminate amebae by lysis, this method utilizes adsorption. This method is often used to filter water solutions from impurities, and it was also found to be effective in trapping bacteria within its structure.11 The effectiveness of micelle–clay complexes against bacteria was discovered after observing the adsorption of E. coli while treating wastewater.12 Among the complexes tested, what seemed to make a difference in the overall effectiveness is the compound that had been complexed to the clay, and the overall stability of the complex itself. For example, the clay that had been complexed with benzyl-dimethyl-hexadecyl-ammonium proved superior to that complexed with octadecyl-trimethyl-ammonium, as more cations were released into the solution.12 Although a plethora of cationic quaternary ammonium salts can be complexed with clay, the use of CPC is desirable due to its safety, FDA approval, and present use in mouthwashes/toothpaste. The use of micelle–clay complexes seems to be pointing toward a promising direction in the development of novel contact lens disinfectants. However, given the little knowledge on the adverse effects on humans of the quaternary ammoniums that have been complexed to the clay thus far, there is a need for a new complex. Here, we propose that a clay complexed with CPC as a promising agent in the effective eradication of Acanthamoeba. CPC is often seen in everyday products such as toothpaste and over the counter mouthwashes in concentrations between 0.045% and 0.1%.8 As it is already approved for the human use, CPC may prove to be a good choice as a quaternary ammonium to be complexed with clay. The inclusion of organoclay made up of CPC and clay may offer a useful avenue in the development of effective contact lens disinfectants, albeit intense future research is needed to investigate its effects on the parasites without harming the human cells together with molecular mode of action, safe consumption in vivo as well as in clinical trials, ocular irritation, and long-term storage and stability, to determine their applied value. The fact that CPC has been incorporated into oral rinses, gels, and toothpastes and commercially used in healthcare products in eliminating bacteria in a few minutes makes it a useful agent in the rational development of contact lens disinfectant.8 As the use of micelle–clay complex for dental hygiene formulations is different from their use for eye-care products, there will be a need for human studies on safety of micelle clay complexes prior to the development of effective contact lens disinfectants containing micelle–clay complexes. Taken together, the use of organoclay made up of CPC and clay in contact lens disinfectants should certainly be the subject of future studies and will likely lead to promising leads for potential applications in the development of effective contact lens disinfectants; however, intensive future research is needed to realize these expectations.