Trichophyton rubrum

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Trichophyton rubrum
Trichophyton rubrum microconidia.jpg
Microconidia of T. rubrum
Scientific classification OOjs UI icon edit-ltr.svg
Domain: Eukaryota
Kingdom: Fungi
Division: Ascomycota
Class: Eurotiomycetes
Order: Onygenales
Family: Arthrodermataceae
Genus: Trichophyton
Species:
T. rubrum
Binomial name
Trichophyton rubrum
(Castell.) Sabour.
Synonyms
  • Trichophyton megniniiR. Blanch. (1895)
  • Trichophyton fischeriJ. Kane (1977)
  • Trichophyton raubitschekiiJ. Kane, Salkin, Weitzman & Smitka (1982)
  • Trichophyton kaneiSummerbell (1987)
  • Epidermophyton purpureum(H. Bang) C.W. Dodge,
  • Sabouraudiella purpurea(H. Bang) Boedijn [1]

Trichophyton rubrum is a dermatophytic fungus in the phylum Ascomycota. It is an exclusively clonal, [2] anthropophilic saprotroph that colonizes the upper layers of dead skin, and is the most common cause of athlete's foot, fungal infection of nail, jock itch, and ringworm worldwide. [3] Trichophyton rubrum was first described by Malmsten  [ sv ] in 1845 and is currently considered to be a complex of species that comprises multiple, geographically patterned morphotypes, several of which have been formally described as distinct taxa, including T. raubitschekii, T. gourvilii, T. megninii and T. soudanense. [4] [5] [6]

Contents

Growth and morphology

Bottom view of a Sabouraud agar plate with a colony of Trichophyton rubrum var. rodhainii. Trichophyton rubrum var. rodhaini PHIL 4248 lores.jpg
Bottom view of a Sabouraud agar plate with a colony of Trichophyton rubrum var. rodhainii.

Typical isolates of T. rubrum are white and cottony on the surface. The colony underside is usually red, although some isolates appear more yellowish and others more brownish. [7] Trichophyton rubrum grows slowly in culture with sparse production of teardrop or peg-shaped microconidia laterally on fertile hyphae. Macroconidia, when present, are smooth-walled and narrowly club-shaped, although most isolates lack macroconidia. [7] Growth is inhibited in the presence of certain sulfur-, nitrogen- and phosphorus-containing compounds. Isolates of T. rubrum are known to produce penicillin in vitro and in vivo. [8]

Variants

Strains of T. rubrum form two distinct biogeographical subpopulations. One is largely restricted to parts of Africa and southern Asia, while the other consists of a population that has spread around the world. Isolates of the Afro-Asiatic subpopulation most commonly manifest clinically as tinea corporis and tinea capitis. [5] In contrast, the globally-distributed subpopulation manifests predominantly in tinea pedis and tinea unguium. [5] Different members of the T. rubrum complex are endemic to different regions; isolates previously referred to T. megninii originate from Portugal, while T. soudanense and T. gourvilii are found in Sub-Saharan Africa. All species included in the T. rubrum complex are "–" mating type with the exception of T. megninii which represents the "+" mating type and is auxotrophic for L-histidine. [5] The mating type identity of T. soudanense remains unknown. [7] Trichophyton raubitschekii, which is common from northwestern India and southeast Asia as well as parts of West Africa, is characterized by strongly granular colonies and is the only variant in the complex that reliably produces urease. [7] In addition to the regioselectivity of these variants of the genus Trichophyton, combinations[ which? ] of varying species of the genus can have multiplicative effects that are invisible to the host immune system, resulting in potentially chronic infection. [9]

Diagnostic tests

Trichophyton rubrum colonies 800.jpg
Colonies of T. rubrum isolated from toenail (left to right): Primary isolation from scrapings on Sabouraud's dextrose agar with cycloheximide, chloramphenicol and gentamicin (14 d); Greenish colonies on Littman Oxgall agar (14 d); Restricted, red colony without pH change on Bromocresol Purple Milk Solids Glucose agar (10 d).
Mentag rubrum violaceum.jpg
Colonies of T. mentagrophytes (left), T. rubrum (center) and T. violaceum (right) showing differential responses on Bromocresol Purple Milk Solids Glucose agar (7 d). T. mentagrophytes shows unrestricted growth with alkaline (purple) colour change, T. rubrum shows restricted growth with no pH change, and T. violaceum produces weak growth accompanied by clearing of the milk solids and a purple colour change.

As a preliminary test indicating infection, plucked hairs and skin and nail scrapings can be directly viewed under a microscope for detection of fungal elements. T. rubrum cannot be distinguished from other dermatophytes in this direct examination. It can be distinguished in vitro from other dermatophytes by means of characteristic micromorphology in culture, usually consisting of small, tear-drop-shaped microconidia, as well as its usual blood-red colony reverse pigmentation on most growth media. In addition, the Bromocresol purple (BCP) milk solid glucose agar test can be used to distinguish it. Different Trichophyton species release different amounts of ammonium ion, altering the pH of this medium. In this test, medium supporting T. rubrum remains sky blue, indicating neutral pH, until 7 to 10 days after inoculation. [7] [10] In primary outgrowth on Sabouraud dextrose agar with cycloheximide and antibacterials, contaminating organisms may cause confusion, as T. rubrum colonies deprived of glucose by competing contaminants may grow without forming the species' distinctive red pigment. [7] Both antibiotic-resistant bacteria and saprotrophic fungi may outcompete T. rubrum for glucose if they contaminate the sample. Red pigment production can be restored in such contaminated isolates using casamino acids erythritol albumin agar (CEA). [7] T. rubrum cultures can be isolated on both cycloheximide-containing media and cycloheximide-free media. The latter are conventionally used for the detection of nail infections caused by non-dermatophytes such as Neoscytalidium dimidiatum . [7] A skin test is ineffective in diagnosing active infection and often yields false negative results. [11]

Pathology

Trichophyton rubrum is rarely isolated from animals. [7] In humans, men are more often infected than women. [12] Infections can manifest as both chronic and acute forms. [10] Typically T. rubrum infections are restricted to the upper layers of the epidermis; however, deeper infections are possible. [13] Approximately 80–93% of chronic dermatophyte infections in many parts of the developed world are thought to be caused by T. rubrum, including cases of tinea pedis (foot), tinea unguium (nail), tinea manuum (hand), tinea cruris (groin), and tinea corporis (arms and leg), as well as some cases of tinea barbae (beard). [5] Trichophyton rubrum has also been known to cause folliculitis in which case it is characterized by fungal element in follicles and foreign body giant cells in the dermis. [10] A T. rubrum infection may also form a granuloma. Extensive granuloma formations may occur in patients with immune deficiencies (e.g. Cushing syndrome). Immunodeficient neonates are susceptible to systemic T. rubrum infection. [10]

Trichophyton rubrum infections do not elicit strong inflammatory responses, as this agent suppresses cellular immune responses involving lymphocytes particularly T cells. [10] Mannan, a component of the fungal cell wall, can also suppress immune responses, although the mechanism of action remains unknown. [11] Trichophyton rubrum infection has been associated with the induction of an id reaction in which an infection in one part of the body induces an immune response in the form of a sterile rash at a remote site. [7] The most common clinical forms of T. rubrum infection are described below.

Trichophyton rubrum is one of the most common causes of chronic tinea pedis commonly known as athlete's foot. [12] Chronic infections of tinea pedis result in moccasin foot, in which the entire foot forms white scaly patches and infections usually affect both feet. [10] Individuals with tinea pedis are likely to have infection at multiple sites. [12] Infections can be spontaneously cured or controlled by topical antifungal treatment. Although T. rubrum tinea pedis in children is extremely rare, it has been reported in children as young as two years of age. [13]

Hand

Tinea manuum is commonly caused by T. rubrum and is characterized by unilateral infections of the palm of the hand. [10]

Groin

Along with E. floccosum, T. rubrum is the most common cause of this disease, also known as 'jock itch.' Infections cause reddish brown lesions mainly on the upper thighs and trunk, that are border by raised edge. [10]

Nail

Once considered a rare causative agent, [12] T. rubrum is now the most common cause of invasive fungal nail disease (called onychomycosis or tinea unguium). [10] Nail invasion by T. rubrum tends to be restricted to the underside of the nail plate and is characterized by the formation of white plaques on the lunula that can spread to the entire nail. The nail often thickens and becomes brittle, turns brown or black. [13] Infections by T. rubrum are frequently chronic, remaining limited to the nails of only one or two digits for many years without progression. [12] Spontaneous cure is rare. [12] These infections are usually unresponsive to topical treatments and respond only to systemic therapy.[ citation needed ] Although it is most frequently seen in adults, T. rubrum nail infections have been recorded in children. [12]

Epidemiology

It is thought that Trichophyton rubrum evolved from a zoophilic ancestor, establishing itself ultimately as an exclusive agent of dermatophytosis on human hosts. Genetic analyses of T. rubrum have revealed the presence of heat shock proteins, transporters, metabolic enzymes and a system of up-regulation of key enzymes in the glyoxylate cycle. [3] The species secretes more than 20 different proteases, including exopeptidases and endopeptidases. [13] These proteases allow T. rubrum to digest human keratin, collagen and elastin; they have an optimum pH of 8 and are calcium dependent. [13] Although T. rubrum shares phylogenetic affiliations with other dermatophytes, it has a distinctive protein regulation system.

Transmission

This species has a propensity to infect glabrous (hairless) skin and is only exceptionally known from other sites. [13] Transmission occurs via infected towels, linens, clothing (contributing factors are high humidity, heat, perspiration, diabetes mellitus, obesity, friction from clothes). [12] Infection can be avoided by lifestyle and hygiene modifications such as avoiding walking barefoot on damp floors particularly in communal areas. [12]

Treatment

Treatment depends on the locus and severity of infection. For tinea pedis, many antifungal creams such as miconazole nitrate, clotrimazole, tolnaftate (a synthetic thiocarbamate), terbinafine hydrochloride, butenafine hydrochloride and undecylenic acid are effective. For more severe or complicated infections, oral ketoconazole was historically shown to be an effective treatment for T. rubrum infections but is no longer used for this indication due to the risk of liver damage as a side effect. [14] Oral terbinafine, itraconazole or fluconazole have all been shown to be safer, effective treatments. Terbinafine and naftifine (topical creams) have been successfully treated tinea cruris and tinea corporis caused by T. rubrum. [15] Trichophyton rubrum infections have been found to be susceptible to photodynamic treatment, [16] laser irradiation, [17] and photoactivation of rose bengal dye by green laser light. [18]

Tinea unguium presents a much greater therapeutic challenge as topical creams do not penetrate the nail bed. Historically, systemic griseofulvin treatment showed improvements in some patients with tinea unguium; however, failure was common even in lengthy treatment courses (e.g., > 1 yr). Current treatment modalities include oral terbinafine, oral itraconazole, and intermittent "pulse therapy" with oral itraconazole [19] [20] Fingernail infections can be treated in 6–8 weeks while toenail infections may take up to 12 weeks to achieve cure. [12] Topical treatment by occlusive dressing combining 20% urea paste with 2% tolnaftate have also shown promise in softening the nail plate to promote penetration of the antifungal agent to the nail bed. [12]

Related Research Articles

<span class="mw-page-title-main">Tinea cruris</span> Fungal infection

Tinea cruris, also known as jock itch, is a common type of contagious, superficial fungal infection of the groin and buttocks region, which occurs predominantly but not exclusively in men and in hot-humid climates.

<span class="mw-page-title-main">Athlete's foot</span> Skin infection caused by fungus

Athlete's foot, known medically as tinea pedis, is a common skin infection of the feet caused by a fungus. Signs and symptoms often include itching, scaling, cracking and redness. In rare cases the skin may blister. Athlete's foot fungus may infect any part of the foot, but most often grows between the toes. The next most common area is the bottom of the foot. The same fungus may also affect the nails or the hands. It is a member of the group of diseases known as tinea.

<span class="mw-page-title-main">Terbinafine</span> Antifungal medication

Terbinafine, sold under the brand name Lamisil among others, is an antifungal medication used to treat pityriasis versicolor, fungal nail infections, and ringworm including jock itch and athlete's foot. It is either taken by mouth or applied to the skin as a cream or ointment. The cream and ointment are not effective for nail infections.

Dermatophyte is a common label for a group of fungus of Arthrodermataceae that commonly causes skin disease in animals and humans. Traditionally, these anamorphic mold genera are: Microsporum, Epidermophyton and Trichophyton. There are about 40 species in these three genera. Species capable of reproducing sexually belong in the teleomorphic genus Arthroderma, of the Ascomycota. As of 2019 a total of nine genera are identified and new phylogenetic taxonomy has been proposed.

<span class="mw-page-title-main">Tinea corporis</span> Medical condition

Tinea corporis is a fungal infection of the body, similar to other forms of tinea. Specifically, it is a type of dermatophytosis that appears on the arms and legs, especially on glabrous skin; however, it may occur on any superficial part of the body.

<span class="mw-page-title-main">Tinea capitis</span> Cutaneous fungal infection of the scalp

Tinea capitis is a cutaneous fungal infection (dermatophytosis) of the scalp. The disease is primarily caused by dermatophytes in the genera Trichophyton and Microsporum that invade the hair shaft. The clinical presentation is typically single or multiple patches of hair loss, sometimes with a 'black dot' pattern, that may be accompanied by inflammation, scaling, pustules, and itching. Uncommon in adults, tinea capitis is predominantly seen in pre-pubertal children, more often boys than girls.

<span class="mw-page-title-main">Ciclopirox</span> Antifungal medication

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<span class="mw-page-title-main">Dermatophytosis</span> Fungal infection of the skin

Dermatophytosis, also known as ringworm, is a fungal infection of the skin. Typically it results in a red, itchy, scaly, circular rash. Hair loss may occur in the area affected. Symptoms begin four to fourteen days after exposure. Multiple areas can be affected at a given time.

<span class="mw-page-title-main">Onychomycosis</span> Medical condition

Onychomycosis, also known as tinea unguium, is a fungal infection of the nail. Symptoms may include white or yellow nail discoloration, thickening of the nail, and separation of the nail from the nail bed. Fingernails may be affected, but it is more common for toenails. Complications may include cellulitis of the lower leg. A number of different types of fungus can cause onychomycosis, including dermatophytes and Fusarium. Risk factors include athlete's foot, other nail diseases, exposure to someone with the condition, peripheral vascular disease, and poor immune function. The diagnosis is generally suspected based on the appearance and confirmed by laboratory testing.

<span class="mw-page-title-main">Tinea manuum</span> Medical condition

Tinea manuum is a fungal infection of the hand, mostly a type of dermatophytosis, often part of two feet-one hand syndrome. There is diffuse scaling on the palms or back of usually one hand and the palmer creases appear more prominent. When both hands are affected, the rash looks different on each hand, with palmer creases appearing whitish if the infection has been present for a long time. It can be itchy and look slightly raised. Nails may also be affected.

<span class="mw-page-title-main">Butenafine</span> Chemical compound

Butenafine, sold under the brand names Lotrimin Ultra, Mentax, and Butop (India), is a synthetic benzylamine antifungal. It is structurally related to synthetic allylamine antifungals such as terbinafine.

<i>Trichophyton</i> Genus of Fungi

Trichophyton is a genus of fungi, which includes the parasitic varieties that cause tinea, including athlete's foot, ringworm, jock itch, and similar infections of the nail, beard, skin and scalp. Trichophyton fungi are molds characterized by the development of both smooth-walled macro- and microconidia. Macroconidia are mostly borne laterally directly on the hyphae or on short pedicels, and are thin- or thick-walled, clavate to fusiform, and range from 4 to 8 by 8 to 50 μm in size. Macroconidia are few or absent in many species. Microconidia are spherical, pyriform to clavate or of irregular shape, and range from 2 to 3 by 2 to 4 μm in size.

<i>Trichophyton tonsurans</i> Species of fungus

Trichophyton tonsurans is a fungus in the family Arthrodermataceae that causes ringworm infection of the scalp. It was first recognized by David Gruby in 1844. Isolates are characterized as the "–" or negative mating type of the Arthroderma vanbreuseghemii complex. This species is thought to be conspecific with T. equinum, although the latter represents the "+" mating strain of the same biological species Despite their biological conspecificity, clones of the two mating types appear to have undergone evolutionary divergence with isolates of the T. tonsurans-type consistently associated with Tinea capitis whereas the T. equinum-type, as its name implies, is associated with horses as a regular host. Phylogenetic relationships were established in isolates from Northern Brazil, through fingerprinting polymorphic RAPD and M13 markers. There seems to be lower genomic variability in the T. tonsurans species due to allopatric divergence. Any phenotypic density is likely due to environmental factors, not genetic characteristics of the fungus.

<span class="mw-page-title-main">Fungal folliculitis</span> Inflammation of hair follicles due to fungal infection

Majocchi's granuloma is a skin condition characterized by deep, pustular plaques, and is a form of tinea corporis. It is a localized form of fungal folliculitis. Lesions often have a pink and scaly central component with pustules or folliculocentric papules at the periphery. The name comes from Domenico Majocchi, who discovered the disorder in 1883. Majocchi was a professor of dermatology at the University of Parma and later the University of Bologna. The most common dermatophyte is called Trichophyton rubrum.

Microsporum nanum is a pathogenic fungus in the family Arthrodermataceae. It is a type of dermatophyte that causes infection in dead keratinized tissues such as skin, hair, and nails. Microsporum nanum is found worldwide and is both zoophilic and geophilic. Animals such as pigs and sheep are the natural hosts for the fungus; however, infection of humans is also possible. Majority of the human cases reported are associated with pig farming. The fungus can invade the skin of the host; if it is scratched off by the infected animal, the fungus is still capable of reproducing in soil.

<span class="mw-page-title-main">Luliconazole</span> Chemical compound

Luliconazole, trade names Luzu among others, is an imidazole antifungal medication. As a 1% topical cream, It is indicated for the treatment of athlete's foot, jock itch, and ringworm caused by dermatophytes such as Trichophyton rubrum, Microsporum gypseum, and Epidermophyton floccosum.

<span class="mw-page-title-main">Favus</span> Medical condition

Favus or tinea favosa is the severe form of tinea capitis, a skin infectious disease caused by the dermatophyte fungus Trichophyton schoenleinii. Typically the species affects the scalp, but occasionally occurs as onychomycosis, tinea barbae, or tinea corporis.

<i>Epidermophyton floccosum</i> Species of fungus

Epidermophyton floccosum is a filamentous fungus that causes skin and nail infections in humans. This anthropophilic dermatophyte can lead to diseases such as tinea pedis, tinea cruris, tinea corporis and onychomycosis. Diagnostic approaches of the fungal infection include physical examination, culture testing, and molecular detection. Topical antifungal treatment, such as the use of terbinafine, itraconazole, voriconazole, and ketoconazole, is often effective.

Topical antifungaldrugs are used to treat fungal infections on the skin, scalp, nails, vagina or inside the mouth. These medications come as creams, gels, lotions, ointments, powders, shampoos, tinctures and sprays. Most antifungal drugs induce fungal cell death by destroying the cell wall of the fungus. These drugs inhibit the production of ergosterol, which is a fundamental component of the fungal cell membrane and wall.

References

  1. ↑ "Trichophyton purpureum H. Bang, - GSD Species". www.speciesfungorum.org. Species Fungorum. Retrieved 8 October 2022.
  2. ↑ Gräser, Y; Kühnisch, J; Presber, W (1999). "Molecular markers reveal exclusively clonal reproduction in Trichophyton rubrum". Journal of Clinical Microbiology. 37 (11): 3713–7. doi:10.1128/jcm.37.11.3713-3717.1999. PMC   85735 . PMID   10523582.
  3. 1 2 Zaugg, C; Monod, M; Weber, J; Harshman, K; Pradervand, S; Thomas, J; Bueno, M; Giddey, K; Staib, P (2009). "Gene expression profiling in the human pathogenic dermatophyte Trichophyton rubrum during growth on proteins". Eukaryotic Cell. 8 (2): 241–50. doi:10.1128/EC.00208-08. PMC   2643602 . PMID   19098130.
  4. ↑ William Williams, The Principles and Practice of Veterinary Surgery, p.734, W.R. Jenkins, 1894, from the collection of the University of California.
  5. 1 2 3 4 5 Gräser, Y; Scott, J; Summerbell, R (2008). "The new species concept in dermatophytes-a polyphasic approach". Mycopathologia. 166 (5–6): 239–56. CiteSeerX   10.1.1.681.6863 . doi:10.1007/s11046-008-9099-y. PMID   18478366. S2CID   3349369.
  6. ↑ Makimura, Koichi; Tamura, Y; Mochizuki, T; Hasegawa, A; Tajiri, Y; Hanazawa, R; Uchida, K; Saito, H; Yamaguchi, H (1999). "Phylogenetic Classification and Species Identification of Dermatophyte Strains Based on DNA Sequences of Nuclear Ribosomal Internal Transcribed Spacer 1 Regions". Journal of Clinical Microbiology. 37 (4): 920–924. doi:10.1128/jcm.37.4.920-924.1999. PMC   88625 . PMID   10074502.
  7. 1 2 3 4 5 6 7 8 9 10 Kane, Julius (1997). Laboratory handbook of dermatophytes : a clinical guide and laboratory handbook of dermatophytes and other filamentous fungi from skin, hair, and nails. Belmont, CA: Star Pub. ISBN   978-0898631579.
  8. ↑ Youssef, N; Wyborn, CH; Holt, G (March 1978). "Antibiotic production by dermatophyte fungi". Journal of General Microbiology. 105 (1): 105–111. doi: 10.1099/00221287-105-1-105 . PMID   632806.
  9. ↑ Martinez DA, Oliver BG, Gräser Y, Goldberg JM, Li W, Martinez-Rossi NM, Monod M, Shelest E, Barton RC, Birch E, Brakhage AA, Chen Z, Gurr SJ, Heiman D, Heitman J, Kosti I, Rossi A, Saif S, Samalova M, Saunders CW, Shea T, Summerbell RC, Xu J, Young S, Zeng Q, Birren BW, Cuomo CA, White TC (2012). "Comparative genome analysis of Trichophyton rubrum and related dermatophytes reveals candidate genes involved in infection". mBio. 3 (5): e00259–12. doi:10.1128/mBio.00259-12. PMC   3445971 . PMID   22951933.
  10. 1 2 3 4 5 6 7 8 9 Weitzman, I; Summerbell, RC (1995). "The dermatophytes". Clinical Microbiology Reviews. 8 (2): 240–59. doi:10.1128/CMR.8.2.240. PMC   172857 . PMID   7621400.
  11. 1 2 Dahl, MV; Grando, SA (1994). "Chronic dermatophytosis: what is special about Trichophyton rubrum?". Advances in Dermatology. 9: 97–109, discussion 110–1. PMID   8060745.
  12. 1 2 3 4 5 6 7 8 9 10 11 DiSalvo, Arthur F (1983). Occupational mycoses . Philadelphia, Pa.: Lea and Febiger. ISBN   978-0812108859.
  13. 1 2 3 4 5 6 Kwon-Chung, K.J.; Bennett, John E. (1992). Medical mycology. Philadelphia: Lea & Febiger. ISBN   9780812114638.
  14. ↑ Lowes, Robert (August 23, 2013). "FDA Safety Changes: Ketoconazole Linked With Liver Injury". Medscape. WebMD LLC. Retrieved November 10, 2018.
  15. ↑ El-Gohary, M; van Zuuren, EJ; Fedorowicz, Z; Burgess, H; Doney, L; Stuart, B; Moore, M; Little, P (2014). "Topical antifungal treatments for tinea cruris and tinea corporis". The Cochrane Database of Systematic Reviews. 8 (8): CD009992. doi:10.1002/14651858.CD009992.pub2. PMID   25090020.
  16. ↑ Huang, H (20 June 2017). "Effect of intense pulsed light on Trichophyton rubrum growth in vitro". Nan Fang Yi Ke da Xue Xue Bao. 37 (6): 853–857. doi:10.3969/j.issn.1673-4254.2017.06.25. PMC   6744133 . PMID   28669966.
  17. ↑ Vural, Emre; Winfield, Harry L.; Shingleton, Alexander W.; Horn, Thomas D.; Shafirstein, Gal (2007). "The effects of laser irradiation on Trichophyton rubrum growth". Lasers in Medical Science. 23 (4): 349–353. doi:10.1007/s10103-007-0492-4. PMID   17902014. S2CID   21874451.
  18. ↑ Cronin, L; Moffitt, M; Mawad, D; Morton, OC; Lauto, A; Stack, C (June 2014). "An in vitro study of the photodynamic effect of rose bengal on trichophyton rubrum". Journal of Biophotonics. 7 (6): 410–7. doi:10.1002/jbio.201200168. PMID   23125143. S2CID   30630519.
  19. ↑ De Doncker, P; Decroix, J; Piérard, GE; Roelant, D; Woestenborghs, R; Jacqmin, P; Odds, F; Heremans, A; Dockx, P; Roseeuw, D (January 1996). "Antifungal pulse therapy for onychomycosis. A pharmacokinetic and pharmacodynamic investigation of monthly cycles of 1-week pulse therapy with itraconazole". Archives of Dermatology. 132 (1): 34–41. doi:10.1001/archderm.132.1.34. PMID   8546481.
  20. ↑ Gupta, AK; Daigle, D; Paquet, M (17 July 2014). "Therapies for Onychomycosis: A Systematic Review and Network Meta-Analysis of Mycological Cure". Journal of the American Podiatric Medical Association. 105 (4): 357–66. doi:10.7547/13-110.1. PMID   25032982.
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