Castellani first described Trichophyton rubrum as epidermphyton rubrum in 1910. It remains the most common dermatomycoses agent. It is an anthropophilic fungus that is the most distributed human dermatophyte (University of Adelaide, 2022). T. rubrum belongs to the Trichophyton genus, Onygenales order, athrodermataceae family, eurotimycetes class, ascomycota phylum, and pezizimytoconita subphylum. In the 19th century, it was believed to cause chronic tinea corpis and has spread all over the globe since then as the tinea Perdis and tinea ungium etiological agent. It remains the most prevalent species out of all dermatophyte infections because it is endemic worldwide except for Antarctica. Trichophyton rubrum is a clonal, anthropophilic saprotroph inhibiting the upper layer of the dead skin. The fungus causes dermatophytoses such as tinea corporis, tinea ungium, tinea pedis, tinea manuum or ochymucosis, and tinea capitis (Zhan et al., 2018). The paper will focus on the Trichophyte rubrum in onychomycosis and treatment using terbinafine drug.
How trichophyton rubrum compromises the nails directly
Trichophyton rubrum includes a keratinophilic filamentous fungus that secretes and produces proteolytic enzymes as vital virulence elements during infection. The proteases can digest the keratins found in skin and nail stratum corneum tissues into short amino acids and peptides for T. rubrum to assimilate and assist the invasion into keratine tissues. T. rubrum remains sensitive to the pH conditions of the environment. Therefore, protease secretion depends on the keratins’ content pH, and in acidic conditions, it is optimal. More so, approximately half of the T.rubrum genome sequence consists of proteases, especially keratinases. In addition, the trichophyton rubrum genome gets grouped into five chromosomes where forty-three special nuclear-encoded genes are analyzed, and almost half are proteases. T. rubrum normally leads to glabrous skin infection resulting in onychomycosis or tinea manuum, tinea pedis, and tinea coporis (Zhan et al., 2018)
Gupta & Stec (2019) highlight that onychomycosis portrays a yellow-brown and white discoloration on the nails. It also presents a violaceous, black, and green discoloration on the nail plate. The infection gets associated with nail detachment from the nail bed, subungual hyperkeratosis, and nail plate thickening. Onychomycosis affects toenails more than fingernails, with the big toe getting more affected. Depending on the invasion pattern, the infection falls into various subtypes. A patient can manifest a combination of the subtypes. T. rubrum causes distal subungual onychomycosis and proximal subungual onychomycosis.
According to Lung et al. (2020), distal subungual onychomycosis, or DSO, remains the most popular. More so, trichophyton rubrum causes DSO infection. The fungal invasion starts at the hyponychium and includes the distal bed and nail plate. Later, the fungus moves proximally via the nail plate leading to spikes or linear channels. Trichophyton rubrum organism migrates via the underlying nail matrix leading to mild inflammation. It further results in subungual hyperkeratosis and focal parakeratosis. As a result, the sub-unitary region thickens, or the nail plate detaches.
Moreover, a subungual space develops as a reservoir for molds and bacteria superinfection (Perugini et al., 2021). Clinically, it manifests as a brownish, whitish, and yellowish discoloration of the nail’s distal corner. One expects onycholysis, distal subungual hyperkeratosis, lateral onychauxis, and nail plate distal aspects.
Piraccini & Alessandrini (2015) notes that the proximal subungual onychomycosis subtype is less common and originates from Trichophyton rubrum. It develops after the fungus invades the proximal nail undersurface fold on the cuticle vicinity and progresses distally. Moreover, the infection presents as a leukonychia area in the proximal nail plate and shifts distally with the growth of the nail. Mainly, it occurs in patients with AIDS and immunodeficiency.
How terbinafine is used in modern-day clinical practice
Maxfield et al. (2022) state that terbinafine entails a synthetic allylamine derivative associated with potent activity against most dermatophytes that impact the nails and skin. The demortophytes include Trichophyton rubrum, Trichophyton mentagrophytes, and epidermophytob floccosum. Terbinafine antifungal activity results from fungal squalene epoxidase increasing the toxic levels of squalene because of expodase selective inhibition in the fungal squalene epoxidase. In 1992, terbinafine was approved in the US in topical form and in 1998 as an oral antifungal. The topical terbinafine has a one percent spray or cream for dermatophyte infection. It treats skin infections, including cruris, tinea pedis, or cop oris. Moreover, oral terbinafine is prescribed and available in 250 mg tablets. It is generically under the Lamisal brand name. The oral prescription is utilized in fungal infection of toe and fingernails or onychomycosis (National Library of Medicine, 2018)
How terbinafine impacts tissue healing in the context of trichophyton rubrum
Oral antifungal treatment remains more successful than topical treatments. However, using the drug, it remains challenging to treat superficial white onychomycosis or some distal onychomycosis infections. Oral therapy is the first line for people who opt for treatment. Itraconazole and terbinafine are considered effective in dermatophyte infection treatment. However, terbinafine is viewed first line (Oakley, n.d). Note that before starting treatment, a laboratory test is recommended. Previously, onychomycosis was treated using griseofulvin, which offered low rates of cure and more extended treatment periods. Current antifungal agents, including itraconazole and terbinafine, remain more effective with a shorter treatment period (Sirgurgersson et al., 2002).
Terbinafine is a topically and orally active antimycotic agent that inhibits the fungi’s ergosterol biosythenisus sterol principal at the squalene epoxidase level. The squalene epoxidase inhibition leads to a fungistatic effect which is the ergosterol-depleted fungal cell membranes, and a fungicidal effect which is the intracellular squalene (Darkes et al., 2003).
Terbinafine has shown effective fungicidal activity on dermatophytes and variable activity on non-dermatophytes and yeasts in vitro. After oral administration, terbinafine gets rapidly absorbed and distributed widely to body tissues, including the nail matrix that is poorly diffused. Nail terbinafine concentrations get detected one week after initiating the therapy and persist for approximately thirty weeks after finishing the treatment. Research indicates that patients using terbinafine treatment attained superior clinical and mycological rates of cure and clinical relapse compared to those treated using intermittent itraconazole (Darkes et al., 2003).
Zaias & Rebell (2004) claim that distal subungual onychomycosis (DSO) nail infection caused by Trichophyton rubrum, terbinafine is an effective antifungal medicine. Terbinafine is given through the mouth to stop the nail from moving in a proximal direction to invade the mycosis in the nail bed in. The nail bed shifts at a similar rate to the overlying nail plate, making the inactive mycotic lesion move distally by the normal development of the nail and, finally, desquamate at the hyponychium. Moreover, the developing new nail and the nail bed near the mycotic nail bed may replace the inactive mycosis that retreats and finally occupy the whole nail bed. At this stage, the DSO is cured completely. However, the cure is confirmed by negative findings under culture analysis and potassium hydroxide. Moreover, the foci of permanent destruction to the nail unit by DSO or any other cause cannot get attributed to the antifungal treatment and do not fail the treatment. Terbinafine remains an effective DSO treatment when pulse-dosed for seven days every three months.
How terbinafine impacts on infection management
Darkes et al. (2003) argue that a randomized, double-blind trial indicated that oral Terbinafine 250 mg daily for twelve to sixteen weeks remains more efficacious compared to griseofulvin, fluconazole, and itraconazole in toenail’s dermatophyte onychomycosis. The mycologic rates of cure and complete rates of cure remained twice as high after treatment using terbinafine. Moreover, terbinafine possess better tolerability than griseoflulvin, fluconazole and intraconazole. In addition, terbinafine possesses a lower potential of the drug to drug interactions compared to azoles, and the greater clinical success of oral terbinafine in treating dermatophyte onychomycosis leads to a cost-effective ratio higher than griseofulvin, fluconazole and itraconazole (Darkes et al., 2003).
Moreover, terbinafine is administered as a progressive therapy at 250 mg daily for twelve weeks in adults for toenail infection and six weeks for fingernail infection. It can get administered as pulse therapy at 500mg daily for four weeks on and 34 weeks off (Maxfield et al., 2022). Progressive terbinafine pulse therapy remains safe and effective in managing dermatophyte toenail onychomycosis in diabetic individuals (Gupta & Stec, 2019).
National Library of Medicine (2018) claims that terbinafine is associated with some side effects. Gastrointestinal impacts, including nausea, skin reactions, dyspepsia, diarrhea, and taste disturbances, remain the most popular serious effects connected to terbinafine. In rare cases, adverse skin reactions and hematological disorders are reported. More so, terbinafine treatment may aggravate psoriasis. Individuals with liver diseases should not undergo terbinafine treatment. More so, terbinafine interacts with some medications. Laboratory confirmation of onychomycosis clinical diagnosis before starting treatment is recommended and is cost-effective.
Darkes, M., Scott, L., & Goa, K. (2003). Terbinafine: A Review of its Use in Onychomycosis in Adults. Am J Clin Dermatol, 4(1): 39-65 . doi: 10.2165/00128071-200304010-00005
Gupta, A., & Stec, N. (2019). Recent Advances in therapies for Onychomycosis and its Management. Version 1. F1000Res 8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600855/
Lueng, A., Lam, J., Leong, K., Hon, K., Barankin, B., & Lueng, A. (2020). Onychomycosis: An Updated Review. Inflamm Allergy Drug Targets, 14(1): 32-45. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509699/
Maxfield, L., Preuss, C., & Bermudez, R. (2022). Terbinafine. StatPearl (Internet) . https://www.ncbi.nlm.nih.gov/books/NBK545218/
National Library of Medicine. (2018). LiverToc: Clinical and Research Information on Drug Induced Liver Injury (Internet). https://www.ncbi.nlm.nih.gov/books/NBK548617/
Perugini, P., Bonettti, M., Guerini, M., Mustelli, G., & Grisoli, P. (2021). A New In Vitro Model to Evaluate Anti-Adhesive Effect against Fungal Nail Infections. Appl. Sci. 11(5), 1977. https://www.mdpi.com/2076-3417/11/5/1977
Piraccini, B., & Alessandrini, A. (2015). Onychomycosis: A Review. J Fungi (Basel), 1(1): 30–43. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770011/
The University of Adelaide. (2022). Mycology. https://www.adelaide.edu.au/mycology/fungal-descriptions-and-antifungal-susceptibility/dermatophytes/trichophyton#trichophyton-rubrum
Zhan, P., Dukik, K., Li, D., K, S., & Stielow. (2018). Phylogeny of dermatophytes with a genomic character evaluation of clinically distinct Trichophyton rubrum and T. violaceum. Studies in Mycology. 2018, 89: 153-17. https://www.sciencedirect.com/science/article/pii/S0166061618300071