A review on clotrimazole in the treatment of fungal infection

 Corresponding author: Bhumika Chandrakar Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution Liscense 4.0. A review on clotrimazole in the treatment of fungal infection Bhumika Chandrakar 1, *, Naveen Kumar Sahu 2, Jyoti Prakash 2, Rukhmani Raman Sahu 2, Hariom Rajput 2 and Gyanesh Kumar Sahu 2 1 Rungta Institute of pharmaceutical Sciences and Research, Kohka, Kurud, Bhilai,490024, Chhattisgarh. 2 Rungta Institute of Pharmaceutical Sciences, Kohka, Kurud, Bhilai,490024, Chhattisgarh. World Journal of Biology Pharmacy and Health Sciences, 2025, 23(02), 223-231 Publication history: Received on 27 June 2025; revised on 11 August 2025; accepted on 13 August 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.23.2.0753 Abstract Mycoses, another name for fungal infections, are caused by pathogenic fungi that can infect many regions of the human body. These infections can be classified as superficial, cutaneous, subcutaneous, or systemic; systemic infections can result in serious and potentially fatal diseases. Human infections are frequently caused by fungi, including dermatophytes, Aspergillus, Candida, and Cryptococcus. Immunocompromised conditions (e.g., HIV/AIDS, organ transplantation, chemotherapy), diabetes, and long-term use of corticosteroids or broad-spectrum antibiotics are risk factors for fungal infections. Depending on the species of fungus and the infection site, the clinical symptoms can range from minor skin diseases to serious, widespread infections that impact internal organs such as the heart, brain, and lungs. Molecular methods, microbiological cultures, and clinical examination are commonly used in diagnosis. Among the available treatments are antifungal. Keywords: Fungal Infection; Clotrimazole; Allylamine; Mycoses 1. Introduction Fungal infections are any disease or condition you get from a fungus. They usually affect your skin, hair, nails or mucous membranes but they can also infect your lungs or other parts of your body. You’re at higher risk for fungal infections if you have a weakened immune system.[1] Fungal infections are of serious public health concern. The incidence of fungal infections in patients with other diseases including Covid-19 is associated with life-threatening mycoses and mortality. [2] Fungal infections can include superficial, cutaneous, sub-cutaneous, mucosal and systemic infections with varying degree of severity. Organisms such as Candida spp. are part of human microbiota that can cause opportunistic infections in individuals and life threatening infections (invasive candidiasis) in immuno-compromised patients such as HIV patients, cancer patients receiving chemotherapy, and patients receiving immuno-suppressive drugs. Besides, opportunistic and systemic infections, fungal pathogens such as Candida, Aspergillus, Fusarium, Mucorales and molds can cause healthcare-associated infections (HAI) in patients with underlying diseases. [3] World Journal of Biology Pharmacy and Health Sciences, 2025, 23(02), 223-231 224 2. Classification Figure 1 Classifications of skin fungal infection [4] 3. Risk factor 3.1. Environment • Living in a warm or wet climate, or in places with damp public spaces like showers and locker rooms. 3.2. Clothing • Wearing tight or non-breathable clothing or footwear. 3.3. Activities • Participating in activities that involve frequent skin-to-skin contact, or activities that involve contact with soil or dust. [5] 3.4. Immune system • Having a weakened immune system due to medical conditions or treatments, such as HIV/AIDS, cancer, chronic lung disease, diabetes, or poor circulation. 3.5. Medications • Taking antibiotics, chemotherapy, radiation therapy, long-term hospital stays, organ transplants, or long-term corticosteroid use. 3.6. Geography • Living in or traveling to areas where certain fungi that cause infections are found. [6] World Journal of Biology Pharmacy and Health Sciences, 2025, 23(02), 223-231 225 4. SIGN and SYMPTOMS Figure 2 Sign and symptoms of skin fungal infection [7] 5. Pathophysiology Figure 3 Pathophysiology of skin fungal infection [8] World Journal of Biology Pharmacy and Health Sciences, 2025, 23(02), 223-231 226 6. Treatment Fungal infections are typically treated with antifungal medications. 6.1. Antifungal drugs classifications 6.1.1. Polyenes • Nystatin • Amphotericin-B 6.1.2. Azoles • Imidazole’s o Clotrimazole o Miconazole o Ketoconazole 6.1.3. Triazoles • Voriconazole • Posaconazole • Fluconazole • Itraconazole 6.1.4. Allylamine • Terbinafine • Butenafine • Naftifine 6.1.5. Echinocandins • Rezafungin • Micafungin • Caspofungin 6.1.6. Others • Griseofluvin • Flucytosine • Tolnaftate [9] 7. Polyenes Polyenes are the oldest family of antifungal drugs which were introduced as early as in 1950s. [10] many polymers have been isolated from Streptomyces spp., but only Ampho-tericin B (AmpB) remains in widespread use, especially with the advent of its many formulations like liposomal AmpB. [11] topical nystatin and AmpB lipid complex. [12,13] It has been known that polyenes, including Amp B which is a bigger polyene, interact with the membrane sterols, mostly ergosterol, which leads to the formation of aqueous pores. In the case of AmpB, the pore contains an annulus of 8 molecules of AmpB which is hydrophobically attached to the membrane sterols.[14,15] This structure causes the formation of a pore in which the polyene hydroxyl is placed inward and leads to leakage of essential components of cyto-plasm, modified permeation of substances, and thus leads to the death of the fungal cell.[16 Polyenes have shown a wide range of activity. They have exhibited efficiency against Candida spp., Fusarium spp., Aspergillus spp., as well as Mucorales. But at the same time, polyenes have been able to show only limited activity against Scedosporium spp. [17] 7.1. Azoles The activity of azoles is similar to that of polyenes as they also target the fungal cell membrane. Ergosterol, which is an essential component of the fungal cell membrane, maintains its fluidity and asymmetry and thus provides integrity in the cells of fungi.[17] The lack of C-4 methyl groups in the ster-ols is essential for maintaining the integrity of the fungal World Journal of Biology Pharmacy and Health Sciences, 2025, 23(02), 223-231 227 cell membranes. Azoles mainly target the heme protein which co-catalyzes cytochrome P-450-dependent 14ademethylation of lanosterol. [18] 7.2. First generation triazole agents Fluconazole has good overall activity against Candida species and Cryptococcus neoformans. However, resistance to the drug is encountered in certain non-albicans Candida species such as C. krusei and some isolates of C. glabrata. [19] It is available as oral and intravenous formulations. Itraconazole has activity against yeasts and some moulds (including Aspergillus), but is disadvantaged by variable bioavailability and an unpleasant taste. In Australia, two oral formulations (the intravenous preparation is not licensed) are available: capsule, and oral solution. The bioavailability of the capsule form is highly influenced by concomitant food intake, and there is considerable intraand inter-patient variability in plasma drug concentrations; the solution form has a more favourable pharmacokinetic profile. [20,21] 7.3. Second generation triazole agents Voriconazole and posaconazole are second-generation triazoles with an extended spectrum of activity against yeasts, C. neoformans and moulds, including Aspergillus, Scedosporium and Fusarium species. [22,23] Voriconazole is active against fluconazole-resistant Candida species, although cross-resistance has been observed. [24] Cross-resistance with fluconazole is uncommon, and posaconazole is the only azole with clinical activity against zygomycete fungi. [25,26] 8. Allylamine Allylamines are a comparatively newer class of antifun-gals that include naftifine and terbinafine. Terbinafine is both orally and topically effective against dermatophytes (Epidermophyton spp., Microsporum, Trichophyton) and Candida. Allylamines exhibit antifungal activities. by interfering with the biosynthesis of ergosterol, which also leads to the accumulation of the sterol precursor-like squalene and the absence of other intermediates of sterol; therefore, allylamines cause inhibition of synthesis of sterol during squalene epoxidation (a reaction step that catalyzes the squalene epoxidase). [27] The death of the fungal cells is mainly associated with the accumulation of squalene than the deficiency of ergosterol. The increased amount of squalene in the fungal cells can lead to more permeation across the cell membranes, therefore causing interfer-ence with the cellular organization. [28] Terbinafine, when applied topically, causes adverse events like gastrointestinal disturbance, erythema, urticaria, rashes, neutropenia, and musculoskeletal reactions. Similarly, Naftifine has known to cause mild rash, erythema, and moder-ate burning when applied topically in the application area. [29,30] 8.1. Clotrimazole Clotrimazole is currently a field of intensive research for the continued development of pharmaceuticals. There is an opportunity for new indications to be exploited and new formulations to be developed. New drugs such as posaconazole can replace clotrimazol in select, highly invasive fungal infections. The drug has been found to inhibit oral candidiasis for up to 6 hours and thermosensitive formulation of vaginal gel formed by the complexation of beta cyclodextrin clotrimrazole. The use of clotrimazole as the principal compound for design studies in structural preparations is being developed as a pharmaceuit to identify novel clinical indicators of treatment and to improve the administration of manufactured goods. The aim is to identify new clinical indicators that could be used to improve Manufacturing of medicines and pharmaceuticals. Clotrimazole is a widely used antimycotic drug for Candida albicans as well as for other fungal diseases. Its antifungal characteristics were found in the late 1960's. It is sold under several distinct brand names and by different businesses around the world as an active ingredient as a generic medication. Clotrimazole is also utilised in treatment of metronidazole-resistant trichomoniasis in addition to its antimycotic action in order to ease symptoms and demonstrate activity against some gram-positive bacteria. World Journal of Biology Pharmacy and Health Sciences, 2025, 23(02), 223-231 228 Figure 4 Structure of Clotrimazole • Molecular FormulaC22H17ClN2 • Molecular Weight - 344.837 g/mol IUPAC Name - 1-[(2-chlorophenyl) diphenylmethyl]-1H-imidazole The chemical feature of clotrimazole is (Fig. 1). It has 4 aromatic rings attached to an atom in the form of tetrahedral carbon (sp3-hybridised) that is very steric in this atom. An imidazole ring is one of the aromatic groups, and this can facilitate reactions to the electron transfer in biological systems. [3,4] A triphenylmethyl system — a structure known to shape and stabilise racial intermediates – is part of its remaining aromatic rings.[5] One of these rings is replaced with chlorine at C2. Clotrimazole, albeit an Acheral compound, has two phenyl rings, one for R and the other pro S. The interaction with a chiral molecule can distinguish certain enantiotope specificities. n a structure-based mechanical investigation the computer modelling of clotrimazole provided four stable conformers, none of which were fitted with two aromatic rings on the same level.[7] These scientific experiments showed, because of the interactions among substituents at the orthopositions in aromatic rings, that the energy content of a supposed coplanar conformer is quite large and that the structure is exceedingly unstable. 8.2. Therapeutic class and pharmaceutical use Clotrimazole was found in the 1960s to be a member of the azole class of synthetic antimycotic medicines. Azoles are the most widely used class of clinical antimycotic medicinal products. Their chemical structure allows them to split in two classes: imidazole and triazole. The imidazole sub-class of azole medicines contains Clotrimazole. Clotrimazole is the medicine of choice for treatment of tinea pedis, tinea cruris, and tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccose, Microspore canis and C. albicans, in addition to econazole and miconazol.[9] It is also widely used in the topical treatment of vulvovaginal and oropharyngeal candidiasis. 8.3. Pharmaceutical dosage forms and administration Clotrimazole is marketed in the European Union under a number of trade names in topical cream and pessary forms. Other formulations, such as clotrimazole creams, powders, liners, topical solutions and vaginal pills, are provided in the USA. The steroid hydrocortisone or bethamethasone sometimes formulates clotrimazole, and these compound preparations may be branded as coclimasone in some situations.[10] In clotrimazole creams, typical excipients include benzyl alcohol, alcohol cetostearyl, triglyceride in the medium chain and triceteareth-4 phosphate. While the availability of clotrimazole varies somewhat from nation to country, over-the-counter minipreparations are generally available, whereas mixed preparations may require a prescription. Clotrimazole is commonly produced as 1 percent cream, lotion, spray or solution for products for the treatment of fungal skin infections. Normal dosages are 100, 200 mg or 500 mg pessaries administered daily for 6, 3 or 1 days in the treatment of vulvovaginal candidiasis. Applying 1, 2 or 10 percent creams in the vaginal zone may result in similar doses. Clotrimazole lozenges are often developed to include 10 mg of active medicine in the treatment of oropharyngeal candidiasis and are slowly sucked into the drug until it is dissolved 5 times daily throughout 14 days. This dose is reduced to 10 mg three times a day for the time period of immunosuppressive therapy for the preventive prevention of oropharyngeal candidiasis for immunosuppressed patients. World Journal of Biology Pharmacy and Health Sciences, 2025, 23(02), 223-231 229 8.4. Side effects, interactions and contraindications Topical forms of clotrimazole are available as over-the-counter medication and are considered reasonably safe and without serious side effects. However, there have been limited case reports of contact allergic dermatitis with clotrimazole creams that are not attributable to allergies to the vehicles or excipients, but are caused by the active ingredient itself.[11] Intravaginal clotrimazole applied via a pessary may damage latex contraceptives (condoms) necessitating the use of additional contraceptive measures during the period of administration. The most prominent side effects of clotrimazole preparations in current use are those associated with the use of oral lozenges for the treatment of oral candidiasis. These include nausea, vomiting, unpleasant mouth sensations, pruritus and elevation of liver enzymes.[12] Clotrimazole lozenges are not sold in the European Union but are widely available in the USA and other countries. Clotrimazole tablets or capsules designed for swallowing, as opposed to sucking, are no longer used as they were associated with GIT disturbances, dysuria and mental depression. Notably, because of clotrimazole's very limited water solubility and GIT toxicity, other imidazole antifungal drugs have replaced clotrimazole in oral capsule formulations. 8.5. Pharmacological Profile 8.5.1. Mechanism of Action Clotrimazole exerts its antifungal activity by altering cell membrane permeability, apparently by binding with phospholipids in the fungal cell membrane. In contrast to polyene antibiotics (e.g., amphotericin B), the action of clotrimazole is less dependent on the sterol content of the cell membrane. As a result of alteration of permeability, the cell membrane is unable to function as a selective barrier, and potassium and other cellular constituents are lost. 8.5.2. Absorbtion Because clotrimazole is generally not significantly absorbed, drug interactions are not a major issue with its use. 8.5.3. Distribution The topical form is minimally absorbed in the serum and tissues. Clotrimazole is a lipophilic drug, and has been shown to be secreted in breastmilk in animal studies. There are limited data available regarding the volume of distribution following oral troche administration. 8.5.4. Protien Binding 98%. Metabolism: Hepatic (metabolized to inactive metabolites). Elimination: Mainly hepatic. 8.5.5. Half life Clotrimazole was given by mouth in a dose of 1.5 g to 7 healthy subjects and 47 patients and peak blood concentrations of up to 1 ug/ml were detected microbiologically at 2 or 4 hours. The half-life was between 3.5 and 5.5 hours. 8.5.6. Adverse effect Burning, stinging, swelling, irritation, redness, pimple-like bumps, tenderness, or flaking of the treated skin may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly. 9. Conclusion Fungal infections represent a significant and growing global health concern, particularly among immunocompromised individuals. While many fungal infections are superficial and treatable, systemic mycoses can be severe and lifethreatening, necessitating early diagnosis and prompt antifungal therapy. The rise in antifungal resistance poses an additional challenge, making it imperative to explore new therapeutic options and preventive strategies. Improved awareness, timely detection through advanced diagnostic techniques, and appropriate use of antifungal agents are critical to reducing morbidity and mortality associated with fungal infections. 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