Actividad combinada de itraconazol y terbinafina sobre aislamientos clínicos de Neoscytalidium dimidiatum / Combined activity of Itraconazole and Terbinafine over clinical isolates of Neoscytalidium dimidiatum

Resumen Objetivo: Analizar la susceptibilidad de N. dimidiatum ante el efecto combinado de itraconazol y terbinafina. Métodos: Se determinó la concentración mínima inhibitoria y la concentración inhibitoria fraccionada in vitro, mediante el método del tablero de ajedrez, a 15 aislamientos clínicos provenientes de onicomicosis de diferentes pacientes, todos positivos por N. dimidiatum. Se prepararon ensayos por duplicado con diluciones combinadas de los antifúngicos y se evaluó el efecto de ambos fármacos. Resultados: La concentración mínima inhibitoria promedio de solo itraconazol aplicado a los aislamientos fue de 30,83 μg/mL y de 4,49 μg/mL combinado con terbinafina. La concentración mínima inhibitoria promedio de solo terbinafina fue de 0,33 μg/mL y de 0,07 μg/mL combinada con itraconazol. Hay diferencias estadísticamente significativas entre las concentraciones mínimas inhibitorias promedio de los antifúngicos analizados en solitario respecto de las concentraciones mínimas inhibitorias combinadas; para itraconazol (t = 2,958; gl = 14; p = 0,01) y (t = 4,721; gl = 14; p < 0,001) para terbinafina. El uso combinado evidenció 40 % de sinergismo. Conclusiones: La combinación itraconazol-terbinafina presentó un efecto sinérgico total para inhibir el crecimiento de N. dimidiatum; esto ofrece una alternativa terapéutica en el tratamiento de las onicomicosis.

Abstract Aim: Study the combined susceptibility patterns of Neoscytalidium dimidiatum to the effect of Itraconazole and Terbinafine. Background: The Minimum Inhibitory Concentration and Fractional Inhibitory Concentration were determined in vitro by the chessboard method for 15 clinical isolates of onychomycosis, from different patients, all positives for N. dimidiatum. Duplicated trials were prepared with combined dilutions of antifungals and the effect of both drugs was evaluated. Results: The average Minimum Inhibitory Concentration of Itraconazole when applied alone for the isolates was 30.83 μg/mL and 4.49 μg/mL when combined with Terbinafine. The average Minimum Inhibitory Concentration of Terbinafine alone was 0.33 μg/mL and 0.07 μg/mL when combined with Itraconazole. Statistically significant differences were found between the average Minimum Inhibitory Concentrations of the antifungals analyzed alone versus the Minimum Inhibitory Concentrations obtained by mixing both compounds. That is for Itraconazole (t = 2,958; gl = 14; p = 0,01) and (t = 4,721; gl = 14; p <0,001) for Terbinafine. Combined use showed 40 % synergism. Conclusions: The Itraconazole-Terbinafine combination had synergistic effect to inhibit the growth of N. dimidiatum, which offers a therapeutic alternative in the treatment of onychomycoses caused by this fungus.

Onicomicosis en pediatría: actualización y tratamiento / Pediatric onychomycosis: update and management

Resumen: La onicomicosis (OM) es una infección fúngica de las uñas, cuyo principal agente causal es el Tricophytum rubrum. Si bien es una patología infrecuente en niños, se ha observado un aumento en la prevalencia en el último tiempo. Hasta la fecha, existen diversos estudios y guías clínicas de OM en adultos. Sin embargo, la literatura en edad pediátrica es escasa, lo que dificulta el tratamiento en pediatría. En el presente articulo se revisa la literatura actual, los métodos diagnosticos de OM, datos epidemiológicos locales y globales, y se presentan las opciones de tratamiento disponibles conside rando su eficacia y perfil de seguridad en población pediátrica.

Abstract: Onychomycosis (OM) is a fungal infection of the nails, whose main etiologic agent is Trichophytum rubrum. Although, it is an unusual pathology in children, in the last years an increase in its preva lence has been observed. To date, there are several studies and clinical guidelines for OM in adults. However, literature in children is scarce, which makes pediatric treatment difficult. The objective of this publication was to review the current literature in order to establish diagnostic methods for OM, national and international epidemiological data, and to provide treatment options taking into account their efficiency and safety profile in the pediatric population.

In vitro antifungal activity of organic compounds derived from amino alcohols against onychomycosis

Abstract Onychomycosis is a fungal infection of the nail caused by high densities of filamentous fungi and yeasts. Treatment for this illness is long-term, and recurrences are frequently detected. This study evaluated in vitro antifungal activities of 12 organic compounds derived from amino alcohols against standard fungal strains, such as Trichophyton rubrum CCT 5507 URM 1666, Trichophyton mentagrophytes ATCC 11481, and Candida albicans ATCC 10231. The antifungal compounds were synthesized from p-hydroxybenzaldehyde (4a-4f) and p-hydroxybenzoic acid (9a-9f). Minimum inhibitory concentrations and minimum fungicidal concentrations were determined according to Clinical and Laboratory Standards Institute protocols M38-A2, M27-A3, and M27-S4. The amine series 4b-4e, mainly 4c and 4e compounds, were effective against filamentous fungi and yeast (MIC from 7.8 to 312 µg/mL). On the other hand, the amide series (9a-9f) did not present inhibitory effect against fungi, except amide 9c, which demonstrated activity only against C. albicans. This allowed us to infer that the presence of amine group and intermediate carbon number (8C-11C) in its aliphatic side chain seems to be important for antifungal activity. Although these compounds present cytotoxic activity on macrophages J774, our results suggest that these aromatic compounds might constitute potential as leader molecules in the development of more effective and less toxic analogs that could have considerable implications for future therapies of onychomycosis.

Comparative efficacy of continuous and pulse dose terbinafifine regimes in toenail dermatophytosis: A randomized double-blind trial.

Introduction: Dermatophytes are the most frequently implicated agents in toenail onychomycosis and oral terbinafi ne has shown the best cure rates in this condition. The pharmacokinetics of terbinafi ne favors its effi cacy in pulse dosing. Objectives: To compare the effi cacy of terbinafi ne in continuous and pulse dosing schedules in the treatment of toenail dermatophytosis. Methods: Seventy-six patients of potassium hydroxide (KOH) and culture positive dermatophyte toenail onychomycosis were randomly allocated to two treatment groups receiving either continuous terbinafi ne 250 mg daily for 12 weeks or 3 pulses of terbinafi ne (each of 500mg daily for a week) repeated every 4 weeks. Patients were followed up at 4, 8 and12 weeks during treatment and post-treatment at 24 weeks. At each visit, a KOH mount and culture were performed. In each patient, improvement in a target nail was assessed using a clinical score; total scores for all nails and global assessments by physician and patient were also recorded. Mycological, clinical and complete cure rates, clinical effectivity and treatment failure rates were then compared. Results: The declines in target nail and total scores from baseline were signifi cant at each follow-up visit in both the treatment groups. However, the inter-group difference was statistically insignifi cant. The same was true for global assessment indices, clinical effectivity as well as clinical, mycological, and complete cure rates. Limitations: The short follow-up in our study may have led to lower cure rates being recorded. Conclusion: Terbinafi ne in pulse dosing is as effective as continuous dosing in the treatment of dermatophyte toenail onychomycosis.

Onicomicosis por Curvularia lunata var. aeria: presentación de un caso clínico / [Onychomycosis for Curvularia lunata var. aeria: Presentation of a clinical case]

We here report a clinical case of a female patient presenting with a three-month history of a white onychodystrophic lesion of both hallux. The infection was due to a mold, identified as Curvularia lunata var aeria. The Curvularia gender is related to the production of phaeohyphomycosis, Curvularia lunata cause onychomycosis occasionally. The patient was treated with itraconazole 200mg/day, during six month with complete remission of the lesions. In conclusion, it is important to consider these fungi as causative agent of nail mycosis since the initial site of infection may be a pathway for systemic dissemination in inmunocompromised patients

Se presenta el caso clínico de una paciente que consultó por una lesión onicodistrófica blanquecina en ambos hallux, de 3 meses de evolución. El examen micológico determinó que el agente causal de la infección era un moho, Curvularia lunata var. aeria. El género Curvularia se asocia a la producción de feohifomicosis. Curvularia lunata es una especie que ocasionalmente puede producir onicomicosis. Se administró tratamiento por pulsos con itraconazol 200mg/día durante 6 meses, con remisión completa de las lesiones. Es importante tener en cuenta a estos hongos como agentes oportunistas causales de micosis ungueales, ya que el lugar inicial de infección puede significar una vía para la diseminación sistémica en pacientes inmunodeprimidos

Onychomycosis: clinical, mycological and in vitro susceptibility testing of isolates of Trichophyton rubrum

BACKGROUND: Onychomycosis or nail fungal infection is the most common nail disease. Despite the wide range of studies on this condition, it remains difficult to establish the correct diagnosis and effective treatment. OBJECTIVES: To evaluate the efficacy of classical laboratory methods for the diagnosis of onychomycosis, and the in vitro susceptibility of the its main etiological agent to antifungals used in routine. METHODS: Nail samples of 100 patients with clinically suspected feet onychomycosis were collected to confirm the diagnosis by direct mycological examination and fungal culture. In vitro antifungal susceptibility testing was performed against strains of the main dermatophyte isolated by microdilution, according to the standardized protocol (M38-A2 - CLSI) RESULTS: Clinical diagnosis of onychomycosis was confirmed by laboratory analysis in 59% of patients. Of these, 54.2% were positive only in direct mycological examination, 44.1% in direct mycological examination and culture, and one case (1.7%) was positive only in culture, resulting in weak agreement between these tests (Kappa = 0.385; p <0.001) High minimum inhibitory concentration values of fluconazole and itraconazole were observed in 66.7% and 25.0% of isolates of T. rubrum tested. Additionally, high MIC values of terbinafine and ciclopirox was detected in only one isolate, and this was one of the strains in which in vitro activity of itraconazole and fluconazole has not been proven. CONCLUSIONS: Poor agreement was observed between direct mycological examination and culture for the diagnosis of onychomycosis, with direct mycological examination being significantly more sensitive. Except for fluconazole, the other three antifungals tested showed good in vitro activity against clinical isolates of T. rubrum. .

Microsporum spp. onychomycosis: disease presentation, risk factors and treatment responses in an urban population

BACKGROUND: Dermatophytes are the main causative agent of all onychomycosis, but genus Microsporum is infrequent and the risk of acquiring the infection is often associated with exposure to risk factors. OBJECTIVES: To describe clinical characteristics of onychomycosis due to Microsporum onychomycosis in an urban population. METHODS: This was a retrospective analysis of the epidemiological and clinical features of 18Microsporum onychomycosis cases of a total of 4220 of onychomycosis cases diagnosed between May 2008 and September 2011 at the tertiary referral center for mycology in Guatemala. RESULTS: Eighteen cases of Microsporum onychomycosis (M. canis, n=10; M. gypseum, n=7; M. nanum, n=1) were identified (prevalence=0.43%). Infection was limited to nails only and disease duration ranged from 1 month to 20 years (mean=6.55 years). The toenails were affected in all cases except for a single M. gypseum case of fingernail. The most common clinical presentation was distal lateral subungual onychomycosis (12/18) followed by total dystrophic onychomycosis (5/18), and superficial white onychomycosis (1/18). M. gypseumpresented in 6 cases as distal lateral subungual onychomycosis and in 1 case like total dystrophic onychomycosis. Five cases (27.78%) were associated with hypertension, diabetes, and psoriasis. Treatment with terbinafine or itraconazole was effective. Two cases of M. canisdistal lateral subungual onychomycosis responded to photodynamic therapy. CONCLUSION: This is the largest reported series of Microsporum onychomycosis and demonstrates such a disease in an urban population. In 27.78% of the cases risk factors for infection were associated to comorbid states. We also report the first 2 cases of successfully treated M. canis onychomycosis with photodynamic therapy and a rare case of M. canis associated dermatophytoma. .

General aspects of drug interactions with systemic antifungals in a retrospective study sample / Aspectos gerais de interações medicamentosas com antifúngicos sistêmicos em um estudo amostral retrospectivo

A retrospective study evaluating hepatic laboratory alterations and potential drug interactions in patients treated for onychomycosis. We evaluated 202 patients, 82% female. In 273 liver enzyme tests, there were changes in only 6%. Potential drug interactions were identified in 28% of patients for imidazole and 14% for terbinafine. The risk of potential interactions increased with the patient's age and use of multiple drugs.

Estudo retrospectivo avaliando alterações laboratoriais hepáticas e potenciais interações medicamentosas em pacientes tratados para onicomicose. Foram avaliados 202 pacientes, sendo 82% do sexo feminino. Em 273 exames de enzimas hepáticas, houve alterações em apenas 6%. Potenciais interações medicamentosas foram identificadas em 28% dos pacientes para imidazólicos e 14% para terbinafina. O risco de interações potenciais aumentou com a idade do paciente e o uso de múltiplas medicações.

Comparative clinical evaluation of efficacy and safety of a formulation containing ciclopirox 8% in the form of a therapeutic nail lacquer in two different posologies for the treatment of onychomycosis of the toes / Avaliação clínica comparativa da eficácia e da segurança de formulação contendo ciclopirox a 8% na forma de esmalte terapêutico em duas diferentes posologias no tratamento de onicomicoses dos pododáctilos

BACKGROUND: The use of topical antifungal agents in the treatment of onychomycosis is of great value in clinical practice as there are different limitations regarding the use of systemic treatment. OBJECTIVE: To evaluate the efficacy and safety of a nail lacquer formulation containing ciclopirox 8% in two different posologies: the traditional regimen (3/2/1) and a regimen of weekly use. METHODS: A blind, randomized, comparative trial which included 41 patients divided into 02 groups, with Group I using the nail lacquer once weekly and Group II using the traditional regimen (3/2/1). Both groups applied the medication for 06 months. RESULTS: The species most frequently found in groups I and II were Trichophyton rubrum (55% and 61.9%) and Trichophyton mentagrophytes (30% and 19%). There was a tendency to a higher level of treatment resistance by T. mentagrophytes infection in both groups, without any predilection for sex, age, proportion of the nail affected at the beginning of the study, duration of the clinical disease and quantity of nails affected per person. Both groups had significant levels of mycological cure, clinical response and therapeutic success and there was no statistically significant difference between groups I and II (p >0.05). CONCLUSION: The nail lacquer containing ciclopirox 8% was equally effective at a weekly dose when compared to the traditional dosing (3/2/1), allowing a more comfortable regimen.

FUNDAMENTOS: A utilização de antifúngicos tópicos na terapêutica da onicomicose é de grande valor na prática clínica, visto que há diferentes limitações ao uso das opções terapêuticas sistêmicas. OBJETIVO: Avaliar comparativamente a eficácia e a segurança de uma formulação de esmalte de ciclopirox a 8% em dois diferentes esquemas posológicos: o esquema tradicional (3/2/1) e um esquema posológico de uso semanal. MÉTODOS: Foi realizado um estudo cego, comparativo e randomizado que incluiu 41 pacientes, divididos em dois grupos, sendo o grupo I submetido ao esquema posológico de uma vez por semana e o grupo II submetido ao esquema posológico tradicional (3/2/1). Os grupos utilizaram a medicação por 180 dias. RESULTADOS: As espécies mais frequentemente encontradas nos grupos I e II foram Trichophyton rubrum (55% e 61,9%) e Trichophyton mentagrophytes (30% e 19%). Houve tendência de maior resistência ao tratamento pelo T. mentagrophytes nos dois grupos estudados, sem predileção por sexo, idade, proporção de acometimento ungueal inicial, tempo de evolução do quadro ou número de unhas acometidas por indivíduo. Ambas as modalidades apresentaram índices significativos de cura micológica, resposta clínica e sucesso terapêutico, e não houve diferença estatisticamente significante entre os grupos I e II (p > 0,05). CONCLUSÃO: O esmalte contendo ciclopirox a 8% mostrou-se igualmente eficaz na posologia de uma vez por semana quando comparada à posologia tradicional (3/2/1), permitindo um esquema posológico mais confortável.

Onicomicosis por Scopulariopsis brevicaulis: Un hallazgo excepcional de tratamiento complejo / Onychomycosis due to scopulariopsis brevicaulis: a finding with a complex treatment

La infección fúngica de las uñas por un hongo filamentoso no dermatofito como Scopulariopsis brevicaulis es rara y puede ocurrir a menudo en asociación con dermatofitos. Es un hallazgo que clínicamente se confunde con un dermatofito pero no responde a tratamiento convencional, ya que es multirresistente. Se presentan dos casos de pacientes con onicomicosis, no relacionados entre sí, con evolución clínica similar, en los cuales al examen micológico directo se identificaron hifas hialinas de hongos; se les realizó cultivo y microcultivo, donde se aisló Scopulariopsis brevicaulis en dos muestras consecutivas, tomadas con algunos días de intervalo. Se revisaron aspectos de su baja frecuencia, diagnóstico preciso y esquema terapéutico recomendado.

An open randomized comparative study to test the efficacy and safety of oral terbinafine pulse as a monotherapy and in combination with topical ciclopirox olamine 8% or topical amorolfine hydrochloride 5% in the treatment of onychomycosis.

BACKGROUND: Onychomycosis is a fungal infection of nails caused by dermatophytes, yeasts and molds. AIMS: To study the efficacy and safety of oral terbinafine pulse as a monotherapy and in combination with topical ciclopirox olamine 8% or topical amorolfine hydrochloride 5% in onychomycosis. METHODS: A clinical comparative study was undertaken on 96 Patients of onychomycosis during the period between August 2005 to July 2006. Forty-eight patients were randomly assigned in group A to receive oral terbinafine 250 mg, one tablet twice daily for seven days every month (pulse therapy); 24 patients in group B to receive oral terbinafine pulse therapy plus topical ciclopirox olamine 8% to be applied once daily at night on all affected nails; and 24 patients in group C to receive oral terbinafine pulse therapy plus topical amorolfine hydrochloride 5% to be applied once weekly at night on all the affected nails. The treatment was continued for four months. The patients were evaluated at four weekly intervals till sixteen weeks and then at 24 and 36 weeks. RESULTS: We observed clinical cure in 71.73, 82.60 and 73.91% patients in groups A, B and C, respectively; Mycological cure rates against dematophytes were 88.9, 88.9 and 85.7 in groups A, B and C, respectively. The yeast mycological cure rates were 66.7, 100 and 50 in groups A, B and C, respectively. In the case of nondermatophytes, the overall response was poor: one out of two cases (50%) responded in group A, while one case each in group B and group C did not respond at all. CONCLUSION: Terbinafine pulse therapy is effective and safe alternative in treatment of onychomycosis due to dermatophytes; and combination therapy with topical ciclopirox or amorolfine do not show any significant difference in efficacy in comparison to monotherapy with oral terbinafine.

Onicomicosis por Acremonium Kiliense / Onychomycosis by Acremonium Kiliense

El rol de los hongos filamentosos hilalinos no dermatofitos, como agentes causales de onicomicosis, ha sido documentado en las últimas tres décadas por diferentes autores y son considerados oportunistas emergentes. El objetivo de este trabajo es presentar un caso de onicomicosis producido por Acremonium kiliense, cuya evolución fue estudiada. Se presentó al laboratorio de micología un paciente de 18 años de edad de sexo femenino con traumatismo en la uña del primer dedo del pie derecho. Se tomaron muestras seriadas de la lesión para la observación microscópica directa con OHK 40% p/v y para cultivos en Agar Sabouraud, Agar Lactrimel y DTM (medio selectivo para dermatofitos) y con las colonias recuperadas se efectuaron microcultivos. Se implementó tratamiento con ciclopirox laca al 8% combinado al principio con Itraconazol vía oral (100 mg/día), con buena evolución. Es importante tener en cuenta a estos hongos oportunistas como agentes etiológicos potenciales de micosis ungueales, en especial en pacientes inmunodeprimidos, ya que la afección ungueal puede ser la puerta de entrada para la diseminación de la infección.

The role of non-dermatophytic hyaline filamentous fungi as agents of onychomycosis has been documented in the last three decades by different authors, who have considered these fungi emerging opportunists. A 18-year-old female patient with trauma to the first toenail of the right foot came to the mycology laboratory. Serial samples of the lesion were collected for direct microscopic observation using 40% (w/v) potassium hydroxide (KOH) and for culture in Sabouraud agar, Lactrimel agar and DTM (dermatophyte selective medium). Microcultures were grown from the colonies recovered. Treatment with 8% ciclopirox nail lacquer, combined at the beginning with oral administration of itraconazole (100 mg a day), was implemented with good evolution. It is important to consider these opportunist fungi as potential etiological agents for nail mycosis, specially in immunosuppressed patients, since nail disease can be the entry point for the spread of infections.

Study of oral itraconazole and terbinafine pulse therapy in onychomycosis.

In this open, randomized and comparative study, the safety and efficacy of systemic intermittent itraconazole and terbinafine was examined in 30 patients with onychomycosis. The patient with positive mycological culture and also the patients with positive microscopy and negative culture were investigated. Patients were randomly assigned: 15 patients in each group received either 200mg itraconazole or 250 mg terbinafine twice daily during the first week of a 4 weeks cycle. The treatment duration was 16 weeks and was followed-up for 36 weeks. Both the treatment regimen showed significant reduction in onychomycosis affected areas after 8 weeks and maximum reduction was observed at the end of 36 weeks. At the end point of the follow-up period, the clinical cure rates (no residual deformity or with some deformity) were 86.7% in the itraconazole group and 100% in the terbinafine group. The mycological cure rates were 86.7% and 100% respectively. However, no statistically significant differences between the treatment groups were seen in clinical, mycological (P= 0.864) and severity assessment (P= 0.220). Nausea, abdominal cramp, headache, back pain and flu like syndrome are the adverse effects more frequently reported. At least one adverse effect was reported by 17 patients, of them 12 belonged to itraconazole group and 5 to terbinafine group and the difference was statistically significant (P= 0.027). The overall therapeutic effectiveness, safety and cost affectivity were in favor of Terbinafine pulse therapy.

Onychomycosis by Scytalidium dimidiatum: report of two cases in Santa Catarina, Brazil

Onicomicoses se apresentam como infecções fúngicas localizadas, muito freqüentes na prática dermatológica. Na grande maioria das vezes, são causadas por dois grupos: dermatófitos e leveduras do gênero Candida. Entretanto, em um pequeno percentual dos casos, os agentes etiológicos compreendem fungos filamentosos não-dermatófitos, pertencentes a vários gêneros e espécies. O objetivo deste trabalho foi o de apresentar dois casos de onicomicose associados à espécie Scytalidium dimidiatum em pacientes residentes em dois municípios do estado de Santa Catarina, Brasil. São discutidos aspectos relacionados a sua patogênese, epidemiologia, diagnóstico laboratorial e tratamento.

Nail changes and disorders among the elderly.

Nail disorders are frequent among the geriatric population. This is due in part to the impaired circulation and in particular, susceptibility of the senile nail to fungal infections, faulty biomechanics, neoplasms, concurrent dermatological or systemic diseases, and related treatments. With aging, the rate of growth, color, contour, surface, thickness, chemical composition and histology of the nail unit change. Age associated disorders include brittle nails, trachyonychia, onychauxis, pachyonychia, onychogryphosis, onychophosis, onychoclavus, onychocryptosis, onycholysis, infections, infestations, splinter hemorrhages, subungual hematoma, subungual exostosis and malignancies. Awareness of the symptoms, signs and treatment options for these changes and disorders will enable us to assess and manage the conditions involving the nails of this large and growing segment of the population in a better way.