La utilidad clínica de los derivados triazólicos en el tratamiento de las infecciones fúngicas / Clinical usefulness of triazole derivatives in the management of fungal infections

El tratamiento de las infecciones producidas por hongos se limita al uso de un reducido número de moléculas. Si bien, la anfotericina B aún sigue siendo considerada como el antifúngico de referencia, para el tratamiento de estas infecciones, la toxicidad aguda y crónica que produce así como el fallo renal limitan su uso y de alguna manera supuso un empuje a la investigación de nuevas familias de sustancias que pudieran ser empleadas en clínica. Una de esas familias es la de los derivados azólicos, descubierta en la década de los años 70 que fue introducida en la práctica clínica en la década posterior. Aun siendo la familia de antifúngicos más prolífica, la investigación sobre nuevas moléculas más seguras y con un mejor perfil farmacológico a la vez que presenten una mayor actividad frente a un amplio espectro de hongos patógenos y con la mayor cantidad rutas de administración (AU)

Current therapy for mycoses is limited to the use of a relative reduced number of antifungal drugs. Although amphotericin B still remains considered as the “gold standard” for treatment, acute and chronic toxicity, such as impairment of renal function, limits its use and enhances the investigation and clinical use other chemical families of antifungal drugs. One of these chemical class of active drugs are azole derivatives, discovered in 70s and introduced in clinical practice in 80s. Being the most prolific antifungal class, investigation about more molecules, with a safer and better pharmacological profile, active against a wide spectrum of fungi, with a wide range of administration routes gives us some azole representatives (AU)

Perfil de sensibilidad antifúngica in vitro de Scopulariopsis brevicaulis aislados de onicomicosis / In vitro antifungal susceptibility profile of Scopulariopsis brevicaulis isolated from onychomycosis

Se ha estudiado el perfil de actividad antifúngica in vitro de amorolfina (AMR), bifonazol (BFZ), clotrimazol (CLZ), econazol (ECZ), fluconazol (FNZ), itraconazol (ITZ), ketoconazol (KTZ), miconazol (MNZ), oxiconazol (OXZ), tioconazol (TCZ) y terbinafina (TRB) frente a 26 aislamientos clínicos de Scopulariopsis brevicaulis obtenidos de muestras clínicas de pacientes con onicomicosis, por medio de un método estandarizado de microdilución. A pesar de que este hongo filamentoso ha sido descrito como resistente frente a un amplio espectro de antifúngicos, los datos obtenidos muestran una mejor actividad fungistática in vitro de AMR, OXZ y TRB (0,08; 0,3 y 0,35 mg/L, respectivamente) en comparación con la de CLZ (0,47 mg/L), ECZ (1,48 mg/L), MNZ (1,56 mg/L, BFZ (2,8 mg/L), TCZ (3,33 mg/L), KTZ (3,73 mg/L). FNZ (178,47 mg/L) e ITZ (4,7 mg/L) mostraron una reducida actividad antifúngica in vitro. Las CMIs obtenidas muestran la reducida sensibilidad in vitro en general de S. brevicaulis a los antifúngicos utilizados y que son de posible uso para el tratamiento de las onicomicosis con la excepción de AMR, OXZ y TRB (AU9

We studied the in vitro antifungal activity profile of amorolfine (AMR), bifonazole (BFZ), clotrimazole (CLZ), econazole (ECZ), fluconazole (FNZ), itraconazole (ITZ), ketoconazole (KTZ), miconazole (MNZ), oxiconazole (OXZ), tioconazole (TCZ) and terbinafine (TRB) against 26 clinical isolates of Scopulariopsis brevicaulis from patients with onychomycosis by means of an standardized microdilution method. Although this opportunistic filamentous fungi was reported as resistant to several broad-spectrum antifungals agents, obtained data shows a better fungistatic in vitro activity of AMR, OXZ and TRB (0.08, 0.3, and 0.35 mg/L, respectively) in comparison to that of CLZ (0.47 mg/L), ECZ (1.48 mg/L), MNZ (1.56 mg/L, BFZ (2.8 mg/L), TCZ (3.33 mg/L), KTZ (3.73 mg/L). FNZ (178.47 mg/L) and ITZ (4.7 mg/L) showed a reduced in vitro antifungal activity against S. brevicaulis. Obtained MICs show the low in vitro antifungal susceptibility of S. brevicaulis to topical drugs for onychomycosis management, with exceptions (AMR, OZX and TRB) (AU)

[Clinical usefulness of triazole derivatives in the management of fungal infections]. / La utilidad clínica de los derivados triazólicos en el tratamiento de las infecciones fúngicas.

Current therapy for mycoses is limited to the use of a relative reduced number of antifungal drugs. Although amphotericin B still remains considered as the "gold standard" for treatment, acute and chronic toxicity, such as impairment of renal function, limits its use and enhances the investigation and clinical use other chemical families of antifungal drugs. One of these chemical class of active drugs are azole derivatives, discovered in 70s and introduced in clinical practice in 80s. Being the most prolific antifungal class, investigation about more molecules, with a safer and better pharmacological profile, active against a wide spectrum of fungi, with a wide range of administration routes gives us some azole representatives.

[In vitro antifungal susceptibility profile of Scopulariopsis brevicaulis isolated from onychomycosis]. / Perfil de sensibilidad antifúngica in vitro de Scopulariopsis brevicaulis aislados de onicomicosis.

We studied the in vitro antifungal activity profile of amorolfine (AMR), bifonazole (BFZ), clotrimazole (CLZ), econazole (ECZ), fluconazole (FNZ), itraconazole (ITZ), ketoconazole (KTZ), miconazole (MNZ), oxiconazole (OXZ), tioconazole (TCZ) and terbinafine (TRB) against 26 clinical isolates of Scopulariopsis brevicaulis from patients with onychomycosis by means of an standardized microdilution method. Although this opportunistic filamentous fungi was reported as resistant to several broad-spectrum antifungals agents, obtained data shows a better fungistatic in vitro activity of AMR, OXZ and TRB (0.08, 0.3, and 0.35 mg/L, respectively) in comparison to that of CLZ (0.47 mg/L), ECZ (1.48 mg/L), MNZ (1.56 mg/L, BFZ (2.8 mg/L), TCZ (3.33 mg/L), KTZ (3.73 mg/L). FNZ (178.47 mg/L) and ITZ (4.7 mg/L) showed a reduced in vitro antifungal activity against S. brevicaulis. Obtained MICs show the low in vitro antifungal susceptibility of S. brevicaulis to topical drugs for onychomycosis management, with exceptions (AMR, OZX and TRB).

Influencia del grupo ecológico sobre la sensibilidad in vitro de los hongos dermatofitos a los antifúngicos / Influence of the ecological group on the in vitro antifungal susceptibility of dermatophytic fungi

Antecedentes. Los hongos dermatofitos se agrupan en geofílicos (suelo), zoofílicos (animales) y antropofílicos (humanos), dependiendo de la fuente de queratina que pueden utilizar como sustrato nutritivo energético. Objetivos. Se ha estudiado la sensibilidad in vitro de aislamientos clínicos de hongos dermatofitos pertenecientes a los 3 grupos ecológicos frente a antifúngicos utilizados para el tratamiento tópico de las dermatofitosis, con el fin de conocer la influencia del grupo en esta actividad. Métodos. Mediante un micrométodo de dilución en medio líquido se determinó la actividad antifúngica in vitro de 9 antifúngicos de uso tópico: amorolfina (AMR), bifonazol (BFZ), clotrimazol, econazol, ketoconazol, miconazol, oxiconazol, terbinafina (TRB) y tioconazol frente a 124 aislamientos clínicos de hongos dermatofitos pertenecientes a los 3 grupos ecológicos (antropofílicos, zoofílicos y geofílicos). Resultados. La actividad antifúngica in vitro mostró diferencias según el grupo ecológico en el que se dividen los hongos dermatofitos, observándose también un patrón especie dependiente. Conclusiones. Los derivados azólicos mostraron un patrón de actividad similar entre ellos, con mayor actividad frente a los antropofílicos > zoofílicos > geofílicos. La actividad de TRB y AMR, por el contrario, fue: zoofílicos > antropofílicos > geofílicos. TRB y AMR fueron las más activas frente a los 3 grupos y BFZ la menos activa(AU)

Background. Dermatophytes can be divided into geophilic (soil), zoophilic (animals) and anthropophilic (humans) strains, depending on the source of the keratin that they use for nutritional purposes. Aims. The in vitro susceptibility of clinical isolates of dermatophyte fungi has been studied in the 3 ecological groups with several antifungal agents for the topical management of dermatophytoses in order to determine their relationship with the ecological group. Methods. A standardised dilution micromethod in a liquid medium was used for the determination of the in vitro antifungal activity of 9 topical antifungal drugs: amorolfine (AMR), bifonazole (BFZ), clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, terbinafine (TRB) and tioconazole. The in vitro activity was obtained against 124 clinical isolates of dermatophyte moulds from the anthropophilic, zoophilic and geophilic ecological groups. Results. The in vitro antifungal activity was different depending on the ecological group, although a species-dependent profile was also observed. Conclusions. Azole derivatives showed a similar antifungal profile, being more active against anthropophilic dermatophytes > zoophilic > geophilic. Activity of TRB and AMR was different from that of azole derivatives (zoophilic > anthropophilic > geophilic). A higher in vitro antifungal activity against the 3 ecological groups was observed with TRB and AMR, whilst BFZ was the less active drug(AU)

Sertaconazole: an antifungal agent for the topical treatment of superficial candidiasis.

Sertaconazole is a useful antifungal agent against mycoses of the skin and mucosa, such as cutaneous, genital and oral candidiasis and tinea pedis. Its antifungal activity is due to inhibition of the ergosterol biosynthesis and disruption of the cell wall. At higher concentrations, sertaconazole is able to bind to nonsterol lipids of the fungal cell wall, increasing the permeability and the subsequent death of fungal cells. Fungistatic and fungicidal activities on Candida are dose-dependent. The antifungal spectrum of sertaconazole includes deramophytes, Candida, Cryptococcus, Malassezia and also Aspergillus, Scedosporium and Scopulariopsis. Sertaconazole also shows an antimicrobial activity against streptococci, staphylococci and protozoa (Trichomonas). In clinical trials including patients with vulvovaginal candidiasis, a single dose of sertaconazole produced a higher cure rate compared with other topical azoles such as econazole and clotrimazole, in shorter periods. Sertaconazole has shown an anti-inflammatory effect that is very useful for the relief of unpleasant symptoms.

In vitro antifungal activity of topical and systemic antifungal drugs against Malassezia species.

The strict nutritional requirements of Malassezia species make it difficult to test the antifungal susceptibility. Treatments of the chronic and recurrent infections associated with Malassezia spp. are usually ineffective. The objective of this study was to obtain in vitro susceptibility profile of 76 clinical isolates of Malassezia species against 16 antifungal drugs used for topical or systemic treatment. Isolates were identified by restriction fragment length polymorphism. Minimal inhibitory concentrations (MIC) were obtained by a modified microdilution method based on the Clinical Laboratory Standards Institute reference document M27-A3. The modifications allowed a good growth of all tested species. High in vitro antifungal activity of most tested drugs was observed, especially triazole derivatives, except for fluconazole which presented the highest MICs and widest range of concentrations. Ketoconazole and itraconazole demonstrated a great activity. Higher MICs values were obtained with Malassezia furfur indicating a low susceptibility to most of the antifungal agents tested. Malassezia sympodialis and Malassezia pachydermatis were found to be more-susceptible species than M. furfur, Malassezia globosa, Malassezia slooffiae and Malassezia restricta. Topical substances were also active but provide higher MICs than the compounds for systemic use. The differences observed in the antifungals activity and interspecies variability demonstrated the importance to studying the susceptibility profile of each species to obtain reliable information for defining an effective treatment regimen.

[Influence of the ecological group on the in vitro antifungal susceptibility of dermatophytic fungi]. / Influencia del grupo ecológico sobre la sensibilidad in vitro de los hongos dermatofitos a los antifúngicos.

BACKGROUND: Dermatophytes can be divided into geophilic (soil), zoophilic (animals) and anthropophilic (humans) strains, depending on the source of the keratin that they use for nutritional purposes. AIMS: The in vitro susceptibility of clinical isolates of dermatophyte fungi has been studied in the 3 ecological groups with several antifungal agents for the topical management of dermatophytoses in order to determine their relationship with the ecological group. METHODS: A standardised dilution micromethod in a liquid medium was used for the determination of the in vitro antifungal activity of 9 topical antifungal drugs: amorolfine (AMR), bifonazole (BFZ), clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, terbinafine (TRB) and tioconazole. The in vitro activity was obtained against 124 clinical isolates of dermatophyte moulds from the anthropophilic, zoophilic and geophilic ecological groups. RESULTS: The in vitro antifungal activity was different depending on the ecological group, although a species-dependent profile was also observed. CONCLUSIONS: Azole derivatives showed a similar antifungal profile, being more active against anthropophilic dermatophytes > zoophilic > geophilic. Activity of TRB and AMR was different from that of azole derivatives (zoophilic > anthropophilic > geophilic). A higher in vitro antifungal activity against the 3 ecological groups was observed with TRB and AMR, whilst BFZ was the less active drug.

Sertaconazole nitrate shows fungicidal and fungistatic activities against Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum, causative agents of tinea pedis.

The fungistatic and fungicidal activities of sertaconazole against dermatophytes were evaluated by testing 150 clinical isolates of causative agents of tinea pedis, Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum. The overall geometric means for fungistatic and fungicidal activities of sertaconazole against these isolates were 0.26 and 2.26 µg/ml, respectively, although values were higher for T. mentagrophytes than for the others. This is the first comprehensive demonstration of the fungicidal activity of sertaconazole against dermatophytes.

Antifungal activity of posaconazole against Candida spp. and non-Candida clinical yeasts isolates

Se ha determinado la actividad antifúngica in vitro de posaconazol frente a 315 aislamientos clínicos de levaduras y 11 cepas ATCC por medio de un método de difusión en agar (Neosensitabs, Rosco, Dinamarca) basado en el documento CLSI M44-A2. Posaconazol presentó una excelente actividad frente a las especies de Cryptococcus y Rhodotorula, como así también, frente a la mayoría de los aislamientos de Candida estudiados. Un total de 13 aislamientos (4,1%) resultaron resistentes: Candida albicans (n=5), Candida glabrata (n=5), Candida tropicalis (n=1), Geotrichum australiensis (n=1) y Geotrichum capitatum (n=1). Nuestros resultados sugieren que posaconazol es un efectivo agente antifúngico frente a las especies de levaduras de mayor relevancia clínica (92,7% de sensibilidad). La técnica de difusión en agar aporta buenas condiciones para la realización de estudios de sensibilidad al posaconazol en la rutina del laboratorio(AU)

The in vitro antifungal activity of posaconazole was tested against 315 yeast clinical isolates and 11 ATCC reference strains by means an agar diffusion method (Neosensitabs, Rosco, Denmark) based in CLSI M44-A2 document. Posaconazole activity was excellent against Cryptococcus and Rhodotorula species studied and showed very good activity against most species of Candida tested. A total of 13 clinical isolates (4.1%) were resistant: Candida albicans (n=5), Candida glabrata (n=5), Candida tropicalis (n=1), Geotrichum australiensis (n=1) and Geotrichum capitatum (n=1). Our results suggest posaconazole is an effective antifungal agent against the most clinically important yeasts species (92.7% of susceptibility). Agar diffusion method provides good conditions for the posaconazole susceptibility study in the routine laboratory(AU)

Antifúngicos disponibles para el tratamiento de las micosis ungueales / Antifungal agents for onychomycoses

Las infecciones fúngicas en las uñas se consideran como uno de los mayores problemas en dermatología. Entre las principales causas están la alta tasa de fracaso terapéutico, las dificultades en el tratamiento y los largos períodos necesarios, los deficientes diagnósticos y seguimiento micológicos, y las alteraciones secundarias de las uñas. Sin embargo, la aparición de nuevos antifúngicos, las nuevas formulaciones, los tratamientos combinados o los nuevos métodos han supuesto mejoras evidentes. No obstante, es imprescindible continuar la investigación en este campo(AU)

Nail fungal infections are considered one of the major dermatological problems due to their high rate of therapeutic failure, management and treatment difficulties. Long-term treatments, inadequate therapies, mycological misdiagnosis and follow-up, secondary alterations of the nail, and resistant microorganisms, are some of the causes of these complications. Although the discovery of new antifungal agents has provided some effective molecules, none of the current available drugs are totally effective. It is important to continue researching in this field to provide new antifungal agents and combined therapies(AU)

[Antifungal agents for onychomycoses]. / Antifúngicos disponibles para el tratamiento de las micosis ungueales.

Nail fungal infections are considered one of the major dermatological problems due to their high rate of therapeutic failure, management and treatment difficulties. Long-term treatments, inadequate therapies, mycological misdiagnosis and follow-up, secondary alterations of the nail, and resistant microorganisms, are some of the causes of these complications. Although the discovery of new antifungal agents has provided some effective molecules, none of the current available drugs are totally effective. It is important to continue researching in this field to provide new antifungal agents and combined therapies.

Terbinafine susceptibility patterns for onychomycosis-causative dermatophytes and Scopulariopsis brevicaulis.

The in vitro antifungal activity of terbinafine against 521 clinical isolates of seven species of dermatophytes, including four onychomycosis-causative species, as well as five Scopulariopsis brevicaulis isolates was determined by a modified Clinical and Laboratory Standards Institute microdilution method. Results showed a high antifungal activity of terbinafine against all dermatophyte isolates (geometric minimal inhibitory concentration (MIC)=0.026 microg/mL; concentration inhibiting 50% of mycological growth (MIC50)=0.03 microg/mL; and concentration inhibiting 90% of mycological growth (MIC90)=0.06 microg/mL). The geometric mean MICs against onychomycosis-causative dermatophyte species was lower (0.024 microg/mL) than the global MIC. However, the in vitro activity of terbinafine against S. brevicaulis was considerably lower (geometric mean MIC=1.38 microg/mL) in comparison with dermatophytes. The antifungal activity of itraconazole was lower than that of terbinafine against these fungi. These data confirm the high in vitro antifungal activity of terbinafine against dermatophytes, under standardised conditions.