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Concept: Onychomycosis

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ABSTRACT Dermatophytes are a uniquely pathogenic group of fungi that cause most common fungal infections globally. The major cause of athlete’s foot is Trichophyton rubrum, a pathogen of human skin. A recent paper in this journal reported the sequencing and analysis of five additional genome sequences, including that of Trichophyton rubrum. These five join the existing two additional genome sequences to bring the total to seven dermatophyte genome sequences, a notable milestone in the study of these fungi. These additional genomes set the stage for future genome-supported studies on the biology, pathogenicity, and host specificity of this important group of pathogens. To predict how this future might play out, we review the history of Aspergillus genomics since the initial publication of the first three Aspergillus genome sequences in 2005, an event that stimulated important studies of the pathogenic Aspergillus species. From these 7 years of Aspergillus history, we offer some speculation on the future of dermatophyte studies supported by the genome sequences given the similarities, differences, and relative levels of support for studies in these two groups of fungi and the diseases they cause.

Concepts: Gene, Bacteria, Future, Pathogen, Trichophyton rubrum, Onychomycosis, Dermatophyte, Fungal diseases

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BACKGROUND: Onychomycosis is a common nail infection, often resulting in nail plate damage and deformity. Topical lacquer treatments have negligible efficacy. Oral treatments, although more efficacious, are limited by drug interactions and potential hepatotoxicity. OBJECTIVE: We investigated the safety and efficacy of efinaconazole 10% solution (efinaconazole), the first triazole antifungal developed for distal lateral subungual onychomycosis. METHODS: Two identical, multicenter, randomized, double-blind, vehicle-controlled studies were conducted in patients with toenail distal lateral subungual onychomycosis (20%-50% clinical involvement [study 1: N = 870, study 2: N = 785]). Patients were randomized (3:1) to efinaconazole or vehicle, once daily for 48 weeks, with 4-week posttreatment follow-up. Debridement was not performed. The primary end point was complete cure rate (0% clinical involvement of target toenail, and both negative potassium hydroxide examination and fungal culture) at week 52. RESULTS: Mycologic cure rates were significantly greater with efinaconazole (study 1: 55.2%, study 2: 53.4%) compared with vehicle (P < .001). The primary end point, complete cure, was also significantly greater for efinaconazole (study 1: 17.8% vs 3.3%, study 2: 15.2% vs 5.5%, P < .001). Treatment success (percent affected target toenail [0%-≤10%]) for efinaconazole ranged from 21.3% to 44.8% in study 1 and from 17.9% to 40.2% in study 2, compared with 5.6% to 16.8% and 7.0% to 15.4%, respectively, with vehicle. Adverse events associated with efinaconazole were local site reactions (2%) and clinically similar to vehicle. LIMITATIONS: A period of 52 weeks may be too brief to evaluate a clinical cure in onychomycosis. CONCLUSIONS: Once daily topical efinaconazole appears to be a viable alternative to oral treatment options for onychomycosis.

Concepts: Pharmacology, Clinical trial, Randomized controlled trial, Effectiveness, Onychomycosis, Nail, Nail disease, Nail plate

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Abstract This is a randomized, double-blind study enrolling 70 patients with onychomycosis of the finger and toenails. Clinical and mycological efficacies as well as measures of safety were assessed monthly for a maximum of 6 months of treatment. The treatment regimens were: fluconazole 1% and fluconazole 1% with urea 40%. These results indicated topical treatment of onychomycosis with a combination of fluconazole 1% and urea 40% was more effective (82.8%) than fluconazole 1% (62.8%) nail lacquer alone in treatment of dermatophytic onychomycosis. Fluconazole was well tolerated and side effects were negligible. At the end of therapy and the end of the 6-month follow-up, fluconazole 1% and urea 40% demonstrated statistically significant superiority in clinical and mycological responses compared with fluconazole 1% alone.

Concepts: Medicine, Effectiveness, Finger, Onychomycosis, Nail, Nail disease, Terbinafine, Itraconazole

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In the framework of a survey on dermatophytoses, 14,619 clinical specimens taken from outpatients with symptoms suggestive of tinea and referred to a Medical Mycology laboratory in Tehran, Iran, were analyzed by direct microscopy and culture. In total, 777 dermatophyte strains recovered in culture were randomly identified by a formerly established RFLP analysis method based on the rDNA ITS regions. For confirmation of species identification, 160 isolates representing the likely entire species spectrum were subjected to ITS-sequencing. Infection was confirmed in 5,175 collected samples (35.4%) by direct microscopy and/or culture. Tinea pedis was the most prevalent type of infection (43.4%), followed by tinea unguium (21.3%), tinea cruris (20.7%), tinea corporis (9.4%), tinea manuum (4.2%), tinea capitis (0.8%) and tinea faciei (0.2%). Trichophyton interdigitale was the most common isolate (40.5%) followed by T. rubrum (34.75%), Epidermophyton floccosum (15.6%), Microsporum canis (3.9%), T. tonsurans (3.5 %) and M. gypseum (0.5%). Other species included M. ferrugineum, T. erinacei, T. violaceum, T. schoenleinii, and a very rare species T. eriotrephon (each one 0.25%). The two strains of T. eriotrephon isolated from tinea manuum and tinea faciei are the second and third reported cases worldwide. Application of DNA-based methods is an important aid in monitoring trends in dermatophytosis in the community.

Concepts: Biology, Trichophyton rubrum, Onychomycosis, Dermatophyte, Fungal diseases, Terbinafine, Mycosis-related cutaneous conditions, Dermatophytosis

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Standard teaching dictates that systemic therapy is required for treatment of onychomycosis. It is unknown whether topical antifungal therapy is effective for pediatric nail infections. This prospective, randomized, double-blind, vehicle-controlled study was conducted in the Pediatric Dermatology Research Unit at Rady Children’s Hospital to determine whether topical antifungal therapy is efficacious for pediatric onychomycosis. Forty patients ages 2 to 16 years with nonmatrix onychomycosis were randomized 1:3 to ciclopirox lacquer or vehicle lacquer. Ciclopirox lacquer or vehicle was applied daily for 32 weeks, with weekly removal of the lacquer and mechanical trimming. Those with poor response were crossed over to active drug at week 12. Thirty-seven patients completed the 32-week study, and follow-up data were collected 1 year after completion of the study from 24 patients. Mycologic cure, effective treatment, and complete cure were assessed, as well as adverse events and effect on quality of life. Mycologic cure was 70% in the treated group and 20% in the vehicle arm (p = 0.03) at week 12. At end of the study (week 32), 77% of treated patients achieved mycologic cure and 71% effective treatment, compared with 22% of the control group. Ninety-two percent of those who were cured and followed for 1 year remained clear. Topical antifungal lacquer (ciclopirox) can be an effective option for children with nonmatrix onychomycosis. Pediatric onychomycosis does not always require systemic therapy and responds better to topical therapy than does adult disease.

Concepts: Medicine, Hospital, Effectiveness, Efficacy, Onychomycosis, Nail, Children's hospital, Nail disease

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Because of the low prevalence of onychomycosis in children, little is known about the efficacy and safety of systemic antifungals in this population. PubMed and Embase databases and the references of related publications were searched in March 2012 for clinical trials (CTs), retrospective analyses (RAs), and case reports (CRs) on the use of systemic antifungals for onychomycosis in children (<18 years). Twenty-six studies (5 CTs, 3 RAs, and 18 CRs) were published between 1976 and 2011. Most of these studies reported the use of systemic terbinafine and itraconazole for the treatment of onychomycosis in children. Therapy with systemic antifungals alone in children age 1 to 17 years resulted in a complete cure rate of 70.8% (n = 151), whereas combined systemic and topical antifungal therapy in one infant and 19 children age 8 and older resulted in a complete cure rate of 80.0% (n = 20). The efficacy and safety profiles of terbinafine, itraconazole, griseofulvin, and fluconazole in children were similar to those previously reported for adults. In conclusion, based on the little information available on onychomycosis in children, systemic antifungal therapies in children are safe and cure rates are similar to the rates achieved in adults.

Concepts: Medicine, Therapy, Antifungals, Antifungal drug, Onychomycosis, Athlete's foot, Fluconazole, Griseofulvin

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Trichophyton rubrum var. raubitschekii is a rare anthropophilic dermatophyte isolated around the world from tinea corporis, tinea cruris, tinea pedis and tinea unguium. In this study, the isolation rate of T. rubrum var. raubitschekii was studied in 200 cases of tinea pedis and tinea unguium in Japan. The 200 clinical isolates were shown to be of downy type as their colonies on Sabouraud’s dextrose agar were white to cream, suede-like to downy, with a yellow-brown to wine-red reverse, and they produced few macroconidia. The type strain of T. rubrum var. raubitschekii (CBS 100084) and one clinical isolate (KMU 8337; isolated at Kanazawa) of downy type tested positive for urease, but the reference strain of T. rubrum (CBS 392.58) and the remaining 199 clinical isolates tested negative. Further epidemiological investigations are required to study human cases of infection with the granular type of T. rubrum and T. rubrum var. raubitschekii in Japan.

Concepts: Biology, Trichophyton rubrum, Onychomycosis, Athlete's foot, Dermatophyte, Fungal diseases, Terbinafine, Mycosis-related cutaneous conditions

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Nail psoriasis is common, occurring in up to half of patients with psoriasis and in 90% of patients with psoriatic arthritis. Left untreated, it may progress to debilitating nail disease, which leads to significant functional impairment. The most common clinical signs of nail psoriasis are nail plate pitting and onycholysis. Other classical signs include oil drop discoloration, subungual hyperkeratosis, and splinter hemorrhages. The modified Nail Psoriasis Severity Index (mNAPSI) can be used to grade the severity of nail psoriasis, while the Nail Psoriasis Quality of Life Scale (NPQ10) is a questionnaire that evaluates the impact of nail psoriasis on the patient’s functional status and quality of life. Treatment of nail psoriasis should be individualized according to the patient’s preferences, severity of nail changes, and presence of skin and/or joint involvement. Both topical and intralesional therapies are safe and effective treatment modalities for nail disease, but are limited by poor adherence and pain, respectively. Systemic therapy such as oral retinoids may be considered for widespread nail disease causing significant morbidity. Among biologic agents, tumor necrosis factor-α inhibitors and T-cell-targeted therapies such as ustekinumab may be useful for refractory severe nail psoriasis.

Concepts: Patient, Psoriatic arthritis, Psoriasis, Onychomycosis, Nail, Nail disease, Conditions of the skin appendages, Psoriatic nails

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Trichophyton rubrum is a worldwide agent responsible for chronic cases of dermatophytosis which have high rates of resistance to antifungal drugs. Attention has been drawn to the antimicrobial activity of aromatic compounds because of their promising biological properties. Therefore, we investigated the antifungal activity of eugenol against 14 strains of T. rubrum which involved determining its minimum inhibitory concentration (MIC) and effects on mycelial growth (dry weight), conidial germination and morphogenesis. The effects of eugenol on the cell wall (sorbitol protect effect) and the cell membrane (release of intracellular material, complex with ergosterol, ergosterol synthesis) were investigated. Eugenol inhibited the growth of 50% of T. rubrum strains employed in this study at an MIC = 256 μg/ml, as well as mycelial growth and conidia germination. It also caused abnormalities in the morphology of the dermatophyte in that we found wide, short, twisted hyphae and decreased conidiogenesis. The results of these studies on the mechanisms of action suggested that eugenol exerts antifungal effects on the cell wall and cell membrane of T. rubrum. Eugenol act on cell membrane by a mechanism that seems to involve the inhibition of ergosterol biosynthesis. The lower ergosterol content interferes with the integrity and functionality of the cell membrane. Finally, our studies support the potential use of the eugenol as an antifungal agent against T. rubrum.

Concepts: Cell membrane, Ergosterol, Antifungal drug, Trichophyton rubrum, Onychomycosis, Athlete's foot, Ketoconazole, Miconazole

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In in vitro tests, natural coniferous resin from the Norway spruce (Picea abies) is strongly antifungal. In this observational study, we tested the clinical effectiveness of a lacquer composed of spruce resin for topical treatment of onychomycosis. Thirty-seven patients with clinical diagnosis of onychomycosis were enrolled into the study. All patients used topical resin lacquer treatment daily for 9 months. A mycological culture and potassium hydroxide (KOH) stain were done from nail samples in the beginning and in the end of the study. Treatment was considered effective, if a mycological culture was negative and there was an apparent clinical cure. At study entry, 20 patients (20/37; 54%; 95% CI: 38-70) had a positive mycological culture and/or positive KOH stain for dermatophytes. At study end, the result of 13 patients was negative (13/19; 68%; 95% CI: 48-89). In one case (1/14; 7%; 95% CI: 0-21) the mycological culture was initially negative, but it turned positive during the study period. By 14 compliant patients (14/32; 44%; 95% CI: 27-61), resin lacquer treatment was considered clinically effective: complete healing took place in three cases (9%) and partial healing in 11 cases (85%). The results indicate some evidence of clinical efficacy of the natural coniferous resin used for topical treatment of onychomycosis.

Concepts: Clinical trial, Effectiveness, Spruce, Pinophyta, Onychomycosis, Christmas tree, Norway Spruce, Picea