Antifungal activities and cytotoxicity studies of six new azasordarins. (17/162)

GW 471552, GW 471558, GW 479821, GW 515716, GW 570009, and GW 587270 are members of a new family of sordarin derivatives called azasordarins. The in vitro activities of these compounds were evaluated against clinical isolates of yeasts, including Candida albicans, Candida non-albicans, and Cryptococcus neoformans strains. Activities against Pneumocystis carinii, Aspergillus spp., less common molds, and dermatophytes were also investigated. Azasordarin derivatives displayed significant activities against the most clinically important Candida species, with the exception of C. krusei. Against C. albicans, including fluconazole-resistant strains, MICs at which 90% of the isolates tested are inhibited (MIC(90)s) were 0.002 microg/ml with GW 479821, 0.015 microg/ml with GW 515716 and GW 587270, and 0.06 microg/ml with GW 471552, GW 471558, and GW 570009. The MIC(90)s of GW 471552, GW 471558, GW 479821, GW 515716, GW 570009, and GW 587270 were 0.12, 0.12, 0.03, 0.06, 0.12, and 0.06 microg/ml, respectively, against C. tropicalis and 4, 0.25, 0.06, 0.25, 0.5, and 0.5 microg/ml, respectively, against C. glabrata. In addition, some azasordarin derivatives (GW 479821, GW 515716, GW 570009, and GW 58720) were active against C. parapsilosis, with MIC(90)s of 2, 4, 4, and 1 microg/ml, respectively. The compounds were extremely potent against P. carinii, showing 50% inhibitory concentrations of 16 microg/ml). These azasordarin derivatives also showed significant activity against emerging fungal pathogens, which affect immunocompromised patients, such as Rhizopus arrhizus, Blastoschizomyces capitatus, and Geotrichum clavatum. Against these organisms, the MICs of GW 587270 ranged from 0.12 to 1 microg/ml, those of GW 479821 and GW 515716 ranged from 0.12 to 2 microg/ml, and those of GW 570009 ranged from 0.12 to 4 microg/ml. Against Fusarium oxysporum, Scedosporium apiospermum, Absidia corymbifera, Cunninghamella bertholletiae, and dermatophytes, GW 587270 was the most active compound, with MICs ranging from 4 to 16 microg/ml. Against Aspergillus spp., the MICs of the compounds tested were higher than 16 microg/ml. The in vitro selectivity of azasordarins was investigated by cytotoxicity studies performed with five cell lines and primary hepatocytes. Concentrations of compound required to achieve 50% inhibition of the parameter considered (Tox(50)s) of GW 570009, GW 587270, GW 479281, and GW 515716 in the cell lines ranged from 60 to 96, 49 to 62, 24 to 36, and 16 to 38 microg/ml, respectively. The cytotoxicity values of GW 471552 and GW 471558 were >100 microg/ml for all cell lines tested. Tox(50)s on hepatocytes were in the following order: GW 471558 > GW 471552 > GW 570009 > GW 587270 > GW 515716 > GW 479821, with values ranging from higher than 100 microg/ml to 23 microg/ml. The cytotoxicity results obtained with fully metabolizing rat hepatocytes were in total agreement with those obtained with cell lines. In summary, the in vitro activities against important pathogenic fungi and the selectivity demonstrated in mammalian cell lines justify additional studies to determine the clinical usefulness of azasordarins.  (+info)

In vitro activity of posaconazole against clinical isolates of dermatophytes. (18/162)

A broth macrodilution method following the recommendations established by the National Committee for Clinical Laboratory Standards was used to compare the in vitro activity of posaconazole (PCZ) with that of itraconazole (ITC) against 30 clinical isolates of dermatophytes belonging to six different species. In terms of MICs, PCZ showed an activity equal to that of ITC. MICs of PCZ at which 50% (MIC(50)) and 90% (MIC(90)) of the isolates were inhibited were 0.5 and > 4.0 microg/ml, respectively. The MIC(50) and MIC(90) of ITC were 1.0 and > 4.0 microg/ml, respectively. However, PCZ showed a more potent fungicidal activity than that of ITC against isolates belonging to the genus Microsporum (P = 0.03). PCZ merits further investigation as a potentially useful agent for treatment of dermatophytosis.  (+info)

Quantitative assay of dermatophyte-infected guinea pig skin scales. (19/162)

A technique to obtain homogeneous suspensions of fungal particles in scrapings from infected skin was devised that permits delivering uniform inocula to culture media being evaluated for suitability as primary isolation media for dermatophytes. The technique consisted of trypsinization of the scales, utilizing scrapings from lesions experimentally induced with an isolate of Trichophyton mentagrophytes var. granulare on guinea pigs. Optimal conditions for dislodging the fungal particles were assessed by colony counts. One-hour treatments with 0.5% (1:300) trypsin yielded the highest counts.  (+info)

An in-office diagnostic procedure to detect dermatophytes in a nationwide study of onychomycosis patients. (20/162)

PURPOSE: To evaluate in-office dermatophyte test medium (DTM) culture as an alternative to traditional laboratory fungal culture for confirming a diagnosis of onychomycosis, and to determine the prevalence of dermatophytes as a cause of onychomycosis in patients not participating in a clinical trial. DESIGN: This nationwide multicenter prospective study enrolled 1100 adult patients with suspect onychomycosis. DTM and laboratory fungal culture results were compared for individual patients. METHODOLOGY: The 310 participating physicians obtained patient nail-bed specimens and divided them for testing by both diagnostic methods. The paired results of the two culture methods were compared using the kappa statistic. PRINCIPAL FINDINGS: Paired culture results were available for 975 of the 1100 enrolled patients. DTM results agreed with central laboratory cultures in 70 percent of cases. The kappa value of 0.40 indicated a moderate degree of correspondence between the two testing modalities. Overall, DTM culture indicated a dermatophyte in 616 patient specimens (56 percent) and central laboratory culture identified a dermatophyte in 528 of the specimens (48 percent). For the entire study population, dermatophytes were identified in 93 percent of the positive central laboratory cultures, confirming that dermatophytes caused the vast majority of the infections. The cost of each DTM culture was approximately $1, compared to $25 for each laboratory fungal culture. CONCLUSION: This study demonstrates that the in-office DTM culture for diagnosing onychomycosis has comparable utility to the traditional laboratory fungal culture, is less expensive, and yields faster results.  (+info)

Two arthroderma benhamiae isolates showing mitochondrial DNA type of Trichophyton verrucosum. (21/162)

Two Trichophyton mentagrophytes isolates from skin lesions on a girl and her rabbit, which were identified as Arthroderma benhamiae by mating tests, were studied by mtDNA (mitochondrial DNA) analysis and sequencing of ITS (internal transcribed spacer) regions of nuclear ribosomal RNA genes. The mtDNA-RFLP (restriction fragment length polymorphism) patterns showed the two isolates to be T. verrucosum rather than A. benhamiae. The ITS sequence showed the isolates to be closer to A. benhamiae Americano-European race than to T. verrucosum and closer to T. verrucosum than to their mating partner A. benhamiae African race. These results suggest that there are three genetic types of A. benhamiae - an Americano-European type, an African type and a T. verrucosum type - and that T. verrucosum is an anamorph of A. benhamiae.  (+info)

Use of the sensititre colorimetric microdilution panel for antifungal susceptibility testing of dermatophytes. (22/162)

The Sensititre YeastOne antifungal panel was used to test 49 dermatophytes belonging to the species Epidermophyton floccosum, Microsporum gypseum, Microsporum canis, Trichophyton tonsurans, Trichophyton rubrum, and Trichophyton mentagrophytes. The MICs of four antifungals obtained with the Sensititre YeastOne antifungal panel were compared with those obtained by the reference NCCLS microdilution method. The levels of agreement between the two methods (+info)

Isolation and genotype analyses of ascospores produced between genetically different Arthroderma benhamiae strains. (23/162)

Thirty-one single ascospore cultures were obtained from one ascoma produced in mating of RV 26678 (+) (Institut de Medicine Tropicale, Antwerp, Belgium) and KMU 4169 (-) (Dept. Dermatology, Kanazawa Medical University, Uchinada, Japan), which are genetically different strains of Arthroderma benhamiae. The isolation was performed with the aid of an inverted microscope and a binocular microscope. The internal transcribed spacer (ITS) regions of the nuclear ribosomal RNA gene of all the ascospore cultures were analyzed by restriction fragment length polymorphism (RFLP) with the restriction enzyme HinfI. The mating types of all the single-ascospore cultures were also checked. Eight cultures had mating type (+) and RV 26678 genotype, 10 had mating type (-) and RV 26678 genotype, 6 had mating type (+) and KMU 4169 genotype and 7 had mating type (-) and KMU 4169 genotype. There was no linkage between the mating types and the genotypes, implying that the genes control the mating behavior and the genes of ribosomal RNA are on different chromosomes from each other. The hybrids comprised half of the isolates and so they were actually from the ascospores and not from the microconidia or the peridial hyphae.  (+info)

In vitro activity of Melaleuca alternifolia (tea tree) oil against dermatophytes and other filamentous fungi. (24/162)

The in vitro activity of Melaleuca alternifolia (tea tree) oil against dermatophytes (n = 106) and filamentous fungi (n = 78) was determined. Tea tree oil MICs for all fungi ranged from 0.004% to 0.25% and minimum fungicidal concentrations (MFCs) ranged from <0.03% to 8.0%. Time-kill experiments with 1-4 x MFC demonstrated that three of the four test organisms were still detected after 8 h of treatment, but not after 24 h. Comparison of the susceptibility to tea tree oil of germinated and non-germinated Aspergillus niger conidia showed germinated conidia to be more susceptible than non-germinated conidia. These data demonstrate that tea tree oil has both inhibitory and fungicidal activity.  (+info)