DERMATOPHYTOSIS: INFECTION AND PREVENTION -A REVIEW

DERMATOPHYTOSIS:  INFECTION AND PREVENTION -A REVIEW

Rajesh Kumar ¹, Shashi Kant Shukla ¹, Anand Pandey ¹, Himanshu Pandey ²,  Ashutosh Pathak ¹ and Anupam Dikshit *¹

Biological Product Laboratory ¹, Botany Department, Faculty of Science, University of Allahabad, Allahabad-211002, Uttar Pradesh, India.

Pharmaceutical Sciences ², Faculty of Health Sciences, SHIATS, Allahabad- 211007, Uttar Pradesh, India

ABSTRACT: The growing impact of infections caused by dermatophytes i.e. Trichophyton, Microsporum and Epidermophyton is not upto the mark in their treatments via conventional methods due to resistance, side effects, and high toxicity. Over prescription and overuse of traditional antifungal agents, high side effects, less eco-friendly nature, high manufacturing costs, high management costs etc., have stimulated the research for alternative natural drugs, such as herbal extract, essential oils and some commercially available compounds. This paper reviews the antidermatophytic activity of various commercially available and conventionally available herbals from different plants and their major role in prevention of prevalent strains dermatophytes. The mode of action of dermatophytes for causing dermatophytosis as well as mode and mechanism of action of various antifungal agents (herbals extracts, oils, suspensions and commercially available compounds) have also proposed. In vitro susceptibility tests and in vivo models used in antidermatophytic assays as well as the mechanism of action of dermatophytes are involved under the perspective of the potential use of herbals as antifungal agents in the clinical treatment of resistance strains responsible for dermatophytosis.

Antifungal activity; Dermatophytosis; Resistance; Herbals; Toxicity,

INTRODUCTION: Superficial fungal infections caused by dermatophytes have increased during the last decades, particularly among high risk patients ¹. The prevalence of these fungal infections have opened to level in last few years that skin mycoses now affect more than 20% populations of the world ². Dermatophytes, include Trichophyton, Microsporum and Epidermophyton, are responsible for major skin infections, sometimes acquiring lifetime risk.

They are a group of keratinophilic fungi that can infect keratinized tissues of human and animals such as skin, hair and nails causing dermatophytoses. These infections are also a major grounds for morbidity-associated superficial mycoses, with recurrent relapses and often refractory to therap ³. Although conventional antifungal drugs are available (azoles, allylamines, and morpholine derivates) for curing of dermatophytosis.

An increasing resistance to these conventional compounds can result in treatment failure. Moreover, the effective life span of classical antifungals is in fact inadequate due to their repeated use as antifungal and immunosuppressive drugs as well as in organ transplantation, lymphomas and HIV secondary infections. Recently, research in aromatic and medicinal plants, and particularly their extracts and essential oils, has attracted many investigators. Essential oils have traditionally been used during centuries for their antifungal propert ⁴. More recently, several studies have shown evidence of the huge potential of these natural products as antifungal agents ^5-10 justifying their current use in a number of pharmaceutical, food and cosmetic products. Therefore, it is not astonishing that essential oils are one of the most talented groups of natural products, for the development of broad-spectrum, cheaper and safer antifungal agents.

Various techniques are available to evaluate the in vitro antidermatophytic activity of essential oils. The agar-based disk diffusion, broth micro-dilution, and vapor phase tests are the mostly used. Also in vivo models have been created in order to access efficiency of in vitro results. Notwithstanding, the widespread use of essential oils by humans and the large evidence, in recent studies, of their potential as complementary or alternative options for prophylaxis and treatments of dermatophytosis, their exact mechanism of action, remains scantily understood. This paper reviews the current knowledge concerning the antidermatophytic activity of essential oils belonging to family.

 Dermatophytes and dermatophytosis:

Dermatophytes may be classified as geophilic, zoophilic and antropophilic on the basis of their main habitat or host. The first group is abundant in soils and is normally associated with decomposing keratinous structures such as hair, feathers, fur, and horns. On the other hand, zoophilic and antropophilic fungi have a more specific distribution and infect animals and humans, respectively ¹¹. Species of the genera Trichophyton, Microsporum and Epidermophyton (Fig. 1) are responsible for common infections in the skin and appendages, generally called dermatophytosis or ringworm infections ^{11, 12}. These fungi colonize keratinized human or animal tissues causing an infection that may vary from mild to very intense. The range of severity depends upon several factors including the host reaction to the metabolic products produced by fungi, the virulence of the infecting strain, the site of infection (tissue keratinization), and also environmental factors ^{13, 14}. The infections are highly prevalent due to the large number of reservoirs (skin, hair, nails), the readiness of transmission from one host to another, and to the high resistance of the strains to adverse environmental conditions. Antropophilic dermatophytes generally coexist in equilibrium on the skin and normally cause only mild irritation. Thus, dermatophytic infections are usually noninvasive, but in immunocompromised patients they can rapidly progress to life-threatening disseminated infections.

Moreover, some zoophilic and geophilic dermatophytes are responsible for quite severe inflammatory reactions due mainly to delayed hypersensitivity responses to fungi proteases. In addition, in recent years, infections have increased considerably among pediatric and geriatric populations ^{15, 16}. Cutaneous dermatophytosis are usually documented by their scaly patches, with central clearing and sharply demarcated, annular, erythematous, sometimes presenting vesicles, blisters and pustules ¹¹.

Nevertheless, in many cases, its analysis is not clinically obvious, requiring mycological analyses, such as direct microscopic observations, fungi isolation and culture, biochemical and physiological tests ¹⁷. In addition, in some cases, it is very difficult to discriminate dermatophytosis from other clinical conditions that also reveal similar symptoms. For example, Tinea corporis may mimic other skin infections such as nummular eczema, subacute cutaneous lupus erythematosus, pustular psoriasis, subcorneal pustular dermatosis, dermatitis, herpes simplex and varicella zoster virus infections ¹⁸ (Fig.1).

Taking into account treatment costs, duration and side effects of conventional agents, an accurate diagnosis is essential to define which treatments must be applied ¹⁷. Classification of human dermatophytosis based on tissue keratinisation at the site of infection, as suggested by scientists ¹⁹. The sites of infection, as well as the common name of the infection, and the species concerned are also indicated. Dermatophytosis is also very common among pets and livestock, yet exceptional in wild animals. Besides the high contagiousness among animal communities and the difficulties in applying effective control measures, long duration of the infection and high costs of treatments are other factors impairing a successful struggle against this disease.

Also of great anxiety is the ability of zoophilic dermatophytes to be transmitted to humans, hence causing serious public health problems. Among the zoophilic species most commonly involved in these infections are Trichophyton mentagrophytes, Trichophyton rubrum ²⁰. Infection of dermatophytosis includes various topical abnormalities Tinea pedis, T. mannum, T. corporis and T. cruris, T. unguium T. capitis (Fig. 2). Freshly, echinocandins have also been used but only for systemic Candida and Aspergillus infections ^{21, 22}.

FIG.1: VARIOUS SYMPTOMS OF DERMATOPHYTOSIS

FIG. 2: CULTURES OF DERMATOPHYTES, A. TRICHOPHYTON MENTAGROPHYTES, B. TRICHOPHYTON RUBRUM,

Superficial mycosis (e.g. Tinea pedis, T. mannum, T. corporis and T. cruris) usually react to topical antifungals ^{3, 11, 23}. Among all the three genera of dermatophytes, Trichophyton is most prevalent strain responsible for dermatophytosis. The most common agents are azoles (eg. clotrimazole, miconazole, econazole, oxiconazole, tioconazole) and allylamines, (e.g. terbinafine and naftifine). Morpholine derivates such as amorolfine and butenafine have been also used ³. With topical medication, primarily mild skin reactions may occur at the site of application ²⁴. For patients displaying wide areas of infection or in cases of severe or constant infections, oral therapy should be considered and the same is true for infections caused by T. unguium and T. capitis, where itraconazole, fluconazole, griseofulvin, and ketoconazole are the subjected antifungals to be used ^{3, 23}.

Some antifungals are inhibitors of enzymes involved in the metabolism of other drugs. For example, it is well known that itraconazole inhibits cytochrome (CYP) 3A4 and, therefore, should not be administrated to patients receiving triazolam, oral midazolam, lovastatin, simvastatin, quinidine or pimozide. Other example is fluconazole which inhibits both CYP 2C9 and CYP 3A4. Thus, cautions should be taken in patients getting phenytoin, warfarin, cyclosporine, and oral sulfonylurea hypoglycemic agents.

Another example is terbinafine a drug that interacts with CYP 1A2 and must not be administered to patients treated with warfarin, nortriptyline or theophylline ^26-28. Also, gastrointestinal interactions may occur with drugs or substances that affect gastric acidity. For example, antacids, histamine-2 receptor blockers, proton pump inhibitors and oral didanosine decrease the absorption of capsule formulations of itraconazole while coca-cola may significantly increase it ²⁸. Bearing in mind to aforementioned grounds it can be concluded that the success of dermatophytosis treatments depends not only of the knowledge of the disease but also of other factors such as clinical pattern and strictness of the infection, causative agent, and possible drug interactions with attendant medications as well as patient’s preference ²⁹.

 Essential oils:

Essential oils are natural composite mixtures of terpenic and non-terpenic compounds. Commonly, monoterpenes and sesquiterpenes as well as their oxygenated derivatives are the major constituents but phenylpropanoids, fatty acids and their esters may also occur ³⁰. These secondary metabolites can be found in various plant organs (flowers, fruits, seeds, leaves, stems, and roots) being produced and stored in different secretory structures. The type of structure (secretory cells, osmophores, secretory cavities, secretory ducts, glandular trichomes or epidermal cells) is closely related to the plant family ³¹.

Anatomical details of these structures are also very relevant to the market value of aromatic plants since they allow the verification of authenticity, detection of substitutions and/or adulterations ³².They play important roles as signaling agents namely in the defense of plants against microorganisms, insects, and herbivores, as attractants of pollinators, and in allelopathic interactions ^{30, 33}. Aromatic plants and their essential oils have traditionally been used since the distant past for their biological properties (bactericidal, fungicidal, virucidal, insecticidal), as well as for cosmetic and medicinal applications ^{30, 34}. In recent years, research on aromatic plants has attracted many researchers and in vitro screening programs, based on ethno-botanical approaches, proved to be very competent in validating traditional uses and providing new ways in the search for active compounds ³⁵. Nowadays many essential oils are commercially valued in the pharmaceutical, food, sanitary, cosmetic, and perfume industries ³⁰.

The largest global markets for medicinal and aromatic plants are China, France, Germany, Italy, Japan, Spain, United Kingdom and United States of America ³⁶. Several methodologies can be employed to extract these oils from plants. However, with reference to the International Standard Organization on Essential Oils ³⁷ they must be obtained exclusively by distillation of plant material using water, steam or dry distillation or by expression. The obtained oils are characterized as volatile liquids, presenting a strong odour, rarely colored, soluble in organic solvents and insoluble in water. Both wild field-growing and cultivated plants can be used to extract essential oils or other secondary metabolites. On the other hand, for ecological reasons, the gathering of large amounts of plants growing in the wild must be avoided since this can harm the species and reduce biodiversity.

Therefore, concentration should be shifted towards the development of effective protocols for plant proliferation in order to produce a large quantity of plants from which chemicals of interest can be extracted thus preventing the exploitation of wild populations ³⁸. These approaches allow large-scale propagation in controlled conditions in any time of the year, hence avoiding damage of natural populations ^39-41. The production of essential oils in plants is under diverse physiological, biochemical, metabolic and genetic regulation ⁴² and generally shows a unpredictable chemical composition due to both intrinsic (sexual, seasonal, ontogenetic, and genetic variations) and extrinsic (ecological and environmental variations) factors ^{43, 44}.

Antidermatophytic activity of essential oils:

Several studies have been available confirming the effect of essential oils and their major compounds on dermatophytic fungi (Trichophyton, Microsporum and Epidermophyton). The most active oils was Thymus serpyllum, Thymus vulgaris, Lavandula latifolia, L. angustifolia. Since this method is performed in sealed conditions and due to difficulties in applying this in vivo, the authors suggested that both potent vapor activity and potent contact activity of the oils would be necessary for anti-infectious therapy ⁵. The in vitro antifungal activity of several commercial Essential oils against clinical strains isolated phase method. Thymus vulgaris and Eugenia caryophyllata (Syzigium aromaticum) oils were the best fungi inhibitors due to the presence of phenolic compounds, namely thymol, carvacrol and eugenol ⁶. Moreover, the antidermatophytic activity of species of Ocimum oil was also evaluated using the agar diffusion method.

Recently, several essential oils were assayed for their antidermatophytic activity, using a microdilution broth test. Synergistic therapy of available antifungal drugs with essential oil has also been assessed ^{45, 46}. However, regarding dermatophytes, a small number of studies are known. Shin and Lim ⁴⁷ evaluated the combination of Pelargonium graveolens essential oil and its main compounds (citronellal and geraniol) with ketoconazole, against Tricophyton spp.

The antifungal activity of ketoconazole was significantly enhanced with the natural compounds and its minimal effective dose was also reduced, hence minimizing possible side-effects. Prun and Shin ⁴⁸ evaluated the synergism between Allium spp. Oils and ketoconazole using both a checkerboard titer and disk diffusion tests. A significant synergism between A. sativum oil and also allicin with this antifungal drug was demonstrated. Khan and Amhad ⁴⁹ explored the combinational effect of several active essential oils and their main compounds with fluconazole against a clinical isolate of T. rubrum. The maximum level of synergism was found between cinnamaldehyde and fluconazole. This compound was able to reduce MIC of fluconazole up to 8-fold and reduce its own MIC up to 32-fold. Also the essential oil of Syzigium aromaticum showed the highest reduction of MIC (up to 128-fold) in combination with fluconazole.

Mechanism of action Essential oils on dermatophytes:

The comprehension of both the mode and mechanism of action of essential oil is important to ensure their usefulness in therapeutic practices. Although these agents have been extensively screened for their antifungal activity, interaction between the oils and microorganisms, which is lately responsible for its activity, is weakly explored. Regarding the few studies on this matter, Candida spp. and Aspergillus spp. have been the species mostly used ⁵⁰ and, therefore, very few information is available for dermatophytes. The main studies on the evaluation of mode and mechanism of action of essential oil on dermatophytes are summarized below.

Pinto et al. (1998) evaluated the ergosterol content of T. rubrum and exhibited that 0.08 μL/mL of Thymus pulegioides oil was able to reduce ergosterol content ⁵¹. A mechanism of action based on impairment of the biosynthesis of ergosterol was recommended as also occurs with conventional azole antifungal drugs ⁵². Pereira et al. ⁵³ through scanning electron microscopic observations showed that essential oil were able to damage the cell membrane and cell wall in a dose and time dependent manner. Park et al. ⁵⁴ analysed the mechanism of action of eugenol, a main compound in Syzygium aromaticum oil.

Modifications in T. mentagrophytes hiphae ultrastructure were observed, namely destruction of inner mitochondrial membranes and cell wall as well as expansion of endoplasmic reticulum near cell membranes, suggesting a mechanism of action through changes in fungal cell structure, particularly at the membrane level. Bajpai et al. ⁵⁵ performed a spore germination assay using several T. rubrum and M. canis strains as well as one strain of T. mentagrophytes. Several oils from lamiaceae was used and showed a strong detrimental effect on all the strains tested. Also another study of the oil was performed on T. rubrum, showing a time-dependent kinetic inhibition of this fungus.

A time-killing dependent assay on T. rubrum IOA-9 to compare the ability of potent essential oil and active compounds with fluconazole carried out. Finally, Transmission Electron Microscopy (TEM) was used to distinguish ultastructural changes in the existence of cinnamaldehyde. Alterations included lysis of cell wall and plasma membranes, endoplasmic reticulum expansion near cell membrane, excessive vacuolization, disintegration of mitochondria, plasma membranes, cell walls, and nuclear and cytoplasmic contents, abnormal distribution of polysaccharides and leakage of cytoplasmic contents.

Generally, the most active antifungal compounds of essential oil are mainly phenolic terpenes such as carvacrol and thymol. These compounds proved to be able to attack cell walls and membranes, affecting the permeability and release of intracellular constituents, as well as several invasive targets, allowing all together embarrassment of fungal infection ⁵⁶.

Many herbal compunds have also shown fungicidal activity against dermatophyte strains. Overall it concludes that the antimicrobial and better bioavailability of herbal extracts as well as essential oils is not due to a single mechanism of action but may result from the effect of different compounds on several cell targets via different modes and mechanisms ^57-58.

It has been reported that proteolytic activity is suppressed in T. rubrum, among other factors, by the availability of free aminoacids, and that proteases with optimal activity in acidic pH are important virulence factors of dermatophytes. A model has been proposed in regulation of proteolytic enzymes by neutral pH during the infectious process of dermatophytosis (Fig. 3). These works suggest that development in keratin and the consequent degration of this protein are somehow regulated by the gene, interfering with the secretion of proteases with optimal activity in alkaline pH. Moreover, pH signaling and monitoring pathways could be considered dermatophyte virulence factors, allowing the development and maintenance of the infection.

FIG. 3: MODEL FOR THE NEUTRAL pH REGULATION OF PROTEOLYTIC ENZYMES SECRETED BY DERMATOPHYTES.

 CONCLUSIONS: Essential oils have proved, in several in vitro assays, to be useful alternatives to conventional antifungal agents having azole groups for the treatment of dermatophytosis. Moreover, it reflects that resistance may occur with their use since multiple mutations are required to overcome all the distinct antifungal actions of each and all of the oils constituents. Conversely, to guarantee their safety, further toxicity studies need to be performed as well as assays to clarify the mechanism of action and possible connections with other antibiotics. The optimization of formulations, the organization of optimal concentrations for clinical applications and the search for possible side-effects are together research lines that need to be explored.

ACKNOWLEDGEMENTS: Thanks are due to the Head, Department of Botany, University of Allahabad, the research facilities; University Grant Commission  New Delhi for providing financial support.

 CONFLICT OF INTEREST: Authors have no conflict of interest.

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    Kumar R, Shukla SK, Pandey A, Pandey H,  Pathak A and Dikshit A: Dermatophytosis:  Infection and Prevention -A Review . Int J Pharm Sci Res 2016; 7(8): 3218-25.doi: 10.13040/IJPSR.0975-8232.7(8).3218-25.

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