ravuconazole and posaconazole

Onychomycosis is a frequent nail disease caused by dermatophytes, yeasts, and nondermatophyte molds. Trichophyton rubrum, T mentagrophytes, and Epidermophyton floccosum are the most common etiologic agents worldwide. Candida spp are the most frequent among the yeasts. Diagnosis is corroborated by direct microscopic examination, culture, and histomycology with periodic acid-Schiff stain. Other new methods of diagnosis are discussed. Treatment is based on oral antifungals: terbinafine, itraconazole, and fluconazole, including other emerging triazole drugs. Therapeutic outcome with ciclopirox and amorolfine lacquers alone and combined with systemic therapy are also reviewed, as well as the new nail enhancers and physical and chemical removal of the diseased nails.

Topics: Administration, Cutaneous; Administration, Oral; Antifungal Agents; Ciclopirox; Drug Administration Schedule; Drug Therapy, Combination; Fluconazole; Foot Dermatoses; Humans; Itraconazole; Mitosporic Fungi; Morpholines; Naphthalenes; Onychomycosis; Pyridones; Pyrimidines; Terbinafine; Thiazoles; Triazoles; Voriconazole

New triazole antifungals (voriconazole, posaconazole, ravuconazole and albaconazole) have been developed to meet the increasing need for new antifungals, and address the rising incidence of invasive fungal infections and the emergence of fungal resistance. This report describes the spectrum of activity of the newer-generation triazoles based on data from in vitro, animal and clinical studies. The authors discuss the use of these agents in combination with other antifungals, the extent of cross-resistance, their toxicity profile and pharmacokinetic properties. A total of two agents are currently available: voriconazole (which is becoming a primary treatment for the management of invasive aspergillosis) and posaconazole (which demonstrates a broad antifungal spectrum). A further two agents, albaconazole and ravuconazole, are undergoing early clinical evaluation and their future is uncertain. For all newer triazoles, concerns about emerging drug-resistant fungi and the incidence and management of breakthrough infections will dictate their role in antifungal prophylaxis and treatment.

Topics: Animals; Antifungal Agents; Aspergillosis; Candidiasis; Cryptococcosis; Drug Administration Schedule; Drug Evaluation, Preclinical; Drug Resistance, Fungal; Drug Therapy, Combination; Humans; Pyrimidines; Randomized Controlled Trials as Topic; Thiazoles; Triazoles; Voriconazole

Fungal pathogens are an increasingly recognized complication of organ transplantation and the ever more potent chemotherapeutic regimens for childhood malignancies. This article provides a brief overview of the current state of systemic antifungal therapy. Currently licensed drugs, including amphotericin B and its lipid derivates; 5-fluorocytosine; the azoles, including fluconazole, itraconazole, and voriconazole; and a representative of the new class of echinocandin agents, caspofungin, are discussed. Newer second-generation azoles (posaconazole and ravuconazole) and echinocandins (micafungin and anidulafungin) that are likely to be licensed in the United States in the next few years also are addressed.

Topics: Age Factors; Amphotericin B; Anidulafungin; Antifungal Agents; Caspofungin; Chemistry, Pharmaceutical; Child; Clinical Trials as Topic; Drug Approval; Drug Resistance, Fungal; Echinocandins; Fluconazole; Flucytosine; Humans; Itraconazole; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Patient Selection; Pediatrics; Peptides, Cyclic; Pyrimidines; Safety; Thiazoles; Triazoles; United States; Voriconazole

Currently, use of standard antifungal therapies can be limited because of toxicity, low efficacy rates, and drug resistance. New formulations are being prepared to improve absorption and efficacy of some of these standard therapies. Various new antifungals have demonstrated therapeutic potential. These new agents may provide additional options for the treatment of superficial fungal infections and they may help to overcome the limitations of current treatments. Liposomal formulations of AmB have a broad spectrum of activity against invasive fungi, such as Candida spp., C. neoformans, and Aspergillus spp., but not dermatophyte fungi. The liposomal AmB is associated with significantly less toxicity and good rates of efficacy, which compare or exceed that of standard AmB. These factors may provide enough of an advantage to patients to overcome the increased costs of these formulations. Three new azole drugs have been developed, and may be of use in both systemic and superficial fungal infections. Voriconazole, ravuconazole, and posaconazole are triazoles, with broad-spectrum activity. Voriconazole has a high bioavailability, and has been used with success in immunocompromised patients with invasive fungal infections. Ravuconazole has shown efficacy in candidiasis in immunocompromised patients, and onychomycosis in healthy patients. Preliminary in vivo studies with posaconazole indicated potential use in a variety of invasive fungal infections including oropharyngeal candidiasis. Echinocandins and pneumocandins are a new class of antifungals, which act as fungal cell wall beta-(1,3)-D-glucan synthase enzyme complex inhibitors. Caspofungin (MK-0991) is the first of the echinocandins to receive Food and Drug Administration approval for patients with invasive aspergillosis not responding or intolerant to other antifungal therapies, and has been effective in patients with oropharyngeal and esophageal candidiasis. Standardization of MIC value determination has improved the ability of scientists to detect drug resistance in fungal species. Cross-resistance of fungal species to antifungal drugs must be considered as a potential problem to future antifungal treatment, and so determination of susceptibility of fungal species to antifungal agents is an important component of information in development of new antifungal agents. Heterogeneity in susceptibility of species to azole antifungals has been noted. This heterogeneity suggests that there are differences in activi

Topics: Administration, Oral; Anidulafungin; Anti-Bacterial Agents; Antifungal Agents; Caspofungin; Chemistry, Pharmaceutical; Drug Approval; Echinocandins; Humans; Lipopeptides; Macrolides; Mycoses; Peptides; Peptides, Cyclic; Pyrimidines; Thiazoles; Triazoles; Voriconazole

Topics: Antifungal Agents; Azoles; Cyclodextrins; Drug Design; Fluconazole; Forecasting; Itraconazole; Japan; Miconazole; Pyrimidines; Thiazoles; Triazoles; Voriconazole

An increase in refractory invasive fungal infections in the setting of marrow/solid organ transplantation and other immune-compromising clinical entities has provided the impetus for the development of new, more efficacious/less toxic antifungal agents. This review (1) examines currently available laboratory methods for the in-vitro evaluation of these new agents against both yeasts and filamentous fungi; (2) provides a summary of the most attractive investigational agents currently undergoing clinical trials/development; and (3) outlines the major refractory mycoses in contemporary medicine.. Fluconazole-resistant Candida spp., Trichosporon spp., zygomycetous genera, the endemic mycoses, Scedosporium, Aspergillus, and Fusarium spp., and an ever-expanding list of lesser-known hyaline and phaeoid genera inciting invasive fungal infections comprise the bulk of refractory mycoses in the immune-compromised host. In-vitro data generated from reference-based antifungal susceptibility testing methods indicate an increased armamentarium of potentially efficacious agents against most of these mycoses.. The newly approved antifungal agents caspofungin and voriconazole, used either as monotherapy or in combination regimens, have a significantly improved spectrum of activity over previously available therapeutic options. Correlation of clinical outcomes with investigational agents demonstrating in-vivo/in-vitro activity will provide critical information needed for the development of clinically significant minimum inhibitory concentration interpretative breakpoints.

Topics: Anti-Bacterial Agents; Antifungal Agents; Caspofungin; Echinocandins; Fungi; Humans; Lipopeptides; Microbial Sensitivity Tests; Mitosporic Fungi; Mycoses; Peptides; Peptides, Cyclic; Pyrimidines; Thiazoles; Triazoles; Voriconazole

Azole antifungal agents are the most common drugs for the treatment of deep seated mycosis throughout the world, because of their favorable anti-fungal spectrum, pharmacokinetics and safety. However there are some weak points in each drug or class, such as emerging resistance or interactions with other drugs. Many new derivatives are now under pre-clinical and clinical evaluation and among them, voriconazole and SCH56592 are showing satisfactory results in their early clinical studies. At the same time, however the ability of doctors to make an appropriate and logical choice for use of these drugs also essential.

Topics: Animals; Antifungal Agents; Azoles; Dosage Forms; Drug Interactions; Drug Resistance, Microbial; Fungi; Humans; Pyrimidines; Thiazoles; Triazoles; Voriconazole

Ergosterol biosynthesis inhibitors, such as posaconazole and ravuconazole, have been proposed as drug candidates for Chagas disease, a neglected infectious tropical disease caused by the protozoan parasite Trypanosoma cruzi. To understand better the mechanism of action and resistance to these inhibitors, a clone of the T. cruzi Y strain was cultured under intermittent and increasing concentrations of ravuconazole until phenotypic stability was achieved. The ravuconazole-selected clone exhibited loss in fitness in vitro when compared to the wild-type parental clone, as observed in reduced invasion capacity and slowed population growth in both mammalian and insect stages of the parasite. In drug activity assays, the resistant clone was above 300-fold more tolerant to ravuconazole than the sensitive parental clone, when the half-maximum effective concentration (EC

Topics: 14-alpha Demethylase Inhibitors; Animals; Cell Line; Chagas Disease; Drug Resistance, Multiple; Genes, Protozoan; Mutation; Nitroimidazoles; Sterol 14-Demethylase; Thiazoles; Triazoles; Trypanocidal Agents; Trypanosoma cruzi

Cytochrome P450 CYP27A1 is the only enzyme in humans converting cholesterol to 27-hydroxycholesterol, an oxysterol of multiple functions, including tissue-specific modulation of estrogen and liver X receptors. Both receptors seem to mediate adverse effects of 27-hydroxycholesterol in breast cancer when the levels of this oxysterol are elevated. The present work assessed druggability of CYP27A1 as a potential antibreast cancer target. We selected 26 anticancer and noncancer medications, most approved by the Food and Drug Administration, and evaluated them first in vitro for inhibition of purified recombinant CYP27A1 and binding to the enzyme active site. Six strong CYP27A1 inhibitors/binders were identified. These were the two antibreast cancer pharmaceuticals anastrozole and fadrozole, antiprostate cancer drug bicalutamide, sedative dexmedetomidine, and two antifungals ravuconazole and posaconazole. Anastrozole was then tested in vivo on mice, which received subcutaneous drug injections for 1 week. Mouse plasma and hepatic 27-hydroxycholesterol levels were decreased 2.6- and 1.6-fold, respectively, whereas plasma and hepatic cholesterol content remained unchanged. Thus, pharmacologic CYP27A1 inhibition is possible in the whole body and individual organs, but does not negatively affect cholesterol elimination. Our results enhance the potential of CYP27A1 as an antibreast cancer target, could be of importance for the interpretation of Femara versus Anastrozole Clinical Evaluation Trial, and bring attention to posaconazole as a potential complementary anti-breast cancer medication. More medications on the US market may have unanticipated off-target inhibition of CYP27A1, and we propose strategies for their identification.

Topics: Adjuvants, Pharmaceutic; Anastrozole; Anilides; Animals; Antifungal Agents; Antineoplastic Agents; Breast Neoplasms; Cholestanetriol 26-Monooxygenase; Dexmedetomidine; Enzyme Inhibitors; Fadrozole; Female; Hypnotics and Sedatives; Mice; Mice, Inbred C57BL; Nitriles; Protein Binding; Thiazoles; Tosyl Compounds; Triazoles

Chagas disease affects more than 10 million people worldwide, and yet, as it has historically been known as a disease of the poor, it remains highly neglected. Two currently available drugs exhibit severe toxicity and low effectiveness, especially in the chronic phase, while new drug discovery has been halted for years as a result of a lack of interest from pharmaceutical companies. Although attempts to repurpose the antifungal drugs posaconazole and ravuconazole (inhibitors of fungal sterol 14α-demethylase [CYP51]) are finally in progress, development of cheaper and more efficient, preferably Trypanosoma cruzi-specific, chemotherapies would be highly advantageous. We have recently reported that the experimental T. cruzi CYP51 inhibitor VNI cures with 100% survival and 100% parasitological clearance both acute and chronic murine infections with the Tulahuen strain of T. cruzi. In this work, we further explored the potential of VNI by assaying nitro-derivative-resistant T. cruzi strains, Y and Colombiana, in highly stringent protocols of acute infection. The data show high antiparasitic efficacy of VNI and its derivative (VNI/VNF) against both forms of T. cruzi that are relevant for mammalian host infection (bloodstream and amastigotes), with the in vivo potency, at 25 mg/kg twice a day (b.i.d.), similar to that of benznidazole (100 mg/kg/day). Transmission electron microscopy and reverse mutation tests were performed to explore cellular ultrastructural and mutagenic aspects of VNI, respectively. No mutagenic potential could be seen by the Ames test at up to 3.5 μM, and the main ultrastructural damage induced by VNI in T. cruzi was related to Golgi apparatus and endoplasmic reticulum organization, with membrane blebs presenting an autophagic phenotype. Thus, these preliminary studies confirm VNI as a very promising trypanocidal drug candidate for Chagas disease therapy.

Topics: 14-alpha Demethylase Inhibitors; Animals; Chagas Disease; Drug Resistance; Endoplasmic Reticulum; Golgi Apparatus; Imidazoles; Male; Mice; Microscopy, Electron, Transmission; Nitroimidazoles; Oxadiazoles; Protozoan Proteins; Sterol 14-Demethylase; Thiazoles; Triazoles; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease, caused by the eukaryotic (protozoan) parasite Trypanosoma cruzi, is an alarming emerging global health problem with no clinical drugs available to treat the chronic stage. Azole inhibitors of sterol 14α-demethylase (CYP51) were proven effective against Chagas, and antifungal drugs posaconazole and ravuconazole have entered clinical trials in Spain, Bolivia, and Argentina. Here we present the x-ray structures of T. cruzi CYP51 in complexes with two alternative drug candidates, pyridine derivatives (S)-(4-chlorophenyl)-1-(4-(4-(trifluoromethyl)phenyl)-piperazin-1-yl)-2-(pyridin-3-yl)ethanone (UDO; Protein Data Bank code 3ZG2) and N-[4-(trifluoromethyl)phenyl]-N-[1-[5-(trifluoromethyl)-2-pyridyl]-4-piperi-dyl]pyridin-3-amine (UDD; Protein Data Bank code 3ZG3). These compounds have been developed by the Drugs for Neglected Diseases initiative (DNDi) and are highly promising antichagasic agents in both cellular and in vivo experiments. The binding parameters and inhibitory effects on sterol 14α-demethylase activity in reconstituted enzyme reactions confirmed UDO and UDD as potent and selective T. cruzi CYP51 inhibitors. Comparative analysis of the pyridine- and azole-bound CYP51 structures uncovered the features that make UDO and UDD T. cruzi CYP51-specific. The structures suggest that although a precise fit between the shape of the inhibitor molecules and T. cruzi CYP51 active site topology underlies their high inhibitory potency, a longer coordination bond between the catalytic heme iron and the pyridine nitrogen implies a weaker influence of pyridines on the iron reduction potential, which may be the basis for the observed selectivity of these compounds toward the target enzyme versus other cytochrome P450s, including human drug-metabolizing P450s. These findings may pave the way for the development of novel CYP51-targeted drugs with optimized metabolic properties that are very much needed for the treatment of human infections caused by eukaryotic microbial pathogens.

Topics: 14-alpha Demethylase Inhibitors; Antiprotozoal Agents; Chagas Disease; Crystallography, X-Ray; Humans; Protozoan Proteins; Sterol 14-Demethylase; Thiazoles; Triazoles; Trypanosoma cruzi

Forty-four isolates belonging to human pathogenic species of Lichtheimia were tested against nine antifungal agents by using the EUCAST methodology. No remarkable differences were found between the clinical species, although L. ramosa showed slightly higher MICs for all drugs. Amphotericin B was the most active drug. Among azole drugs, posaconazole had the best activity in vitro and voriconazole was inactive. Echinocandins showed activity for some isolates, suggesting a potential role in combination therapy.

Topics: Amphotericin B; Antifungal Agents; Humans; Microbial Sensitivity Tests; Mucorales; Pyrimidines; Triazoles; Voriconazole

We have determined the in vitro activities of amphotericin B (AMB), voriconazole, posaconazole (PSC), itraconazole (ITC), ravuconazole, terbinafine, and caspofungin against five strains of Cunninghamella bertholletiae and four of Cunninghamella echinulata. The best activity was shown by terbinafine against both species (MIC range = 0.3 to 0.6 μg/ml) and PSC against Cunninghamella bertholletiae (MIC = 0.5 μg/ml). We have also evaluated the efficacies of PSC, ITC, and AMB in neutropenic and diabetic murine models of disseminated infection by Cunninghamella bertholletiae. PSC at 40, 60, or 80 mg/kg of body weight/day was as effective as AMB at 0.8 mg/kg/day in prolonging survival and reducing the fungal tissue burden in neutropenic mice. PSC at 80 mg/kg/day was more effective than AMB at 0.8 mg/kg/day in reducing the fungal load in brain and lung of diabetic mice. Histological studies revealed an absence of fungal elements in organs of mice treated with either AMB at 0.8 mg/kg/day or PSC at 60 or 80 mg/kg/day in both models. ITC showed limited efficacy in both models. PSC could be a therapeutic option for the treatment of systemic infections caused by Cunninghamella bertholletiae.

Topics: Amphotericin B; Animals; Antifungal Agents; Caspofungin; Cunninghamella; Diabetes Mellitus, Experimental; Echinocandins; Itraconazole; Lipopeptides; Male; Mice; Microbial Sensitivity Tests; Mucormycosis; Pyrimidines; Thiazoles; Triazoles; Voriconazole

The antifungal susceptibility profiles of 77 clinical strains of Mucorales species, identified by internal transcribed spacer sequencing, were analyzed. MICs obtained at 24 and 48 h were compared. Amphotericin B was the most active agent against all isolates, except for Cunninghamella and Apophysomyces isolates. Posaconazole also showed good activity for all species but Cunninghamella bertholletiae. Voriconazole had no activity against any of the fungi tested. Terbinafine showed good activity, except for Rhizopus oryzae, Mucor circinelloides, and Rhizomucor variabilis isolates.

Topics: Amphotericin B; Antifungal Agents; DNA, Ribosomal Spacer; Microbial Sensitivity Tests; Mucorales; Triazoles

The in vitro interaction of antifungals with immunosuppressive drugs was evaluated against zygomycetes. The combination of amphotericin B with cyclosporine, rapamycin, or tacrolimus was synergistic for 90%, 70%, and 30% of the isolates, respectively. For posaconazole, itraconazole, and ravuconazole, synergy was more frequently observed with cyclosporine than with rapamycin or tacrolimus and antagonistic interactions were rarely noted. In summary, calcineurin inhibitors and rapamycin can be synergistic in vitro with amphotericin B and azoles against zygomycetes.

Topics: Amphotericin B; Antifungal Agents; Azoles; Cyclosporine; Drug Interactions; Immunosuppressive Agents; Itraconazole; Microbial Sensitivity Tests; Mucorales; Rhizopus; Sirolimus; Tacrolimus; Thiazoles; Triazoles

A microdilution method was used to test 11 antifungal drugs against clinical isolates of Fusarium thapsinum and three different phylogenetic clades of Fusarium verticillioides that were characterized by sequencing a region of the beta-tubulin gene. Terbinafine was the most-active drug against both species, followed by posaconazole against F. verticillioides.

Topics: Animals; Antifungal Agents; Drug Resistance, Fungal; Fusarium; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Mycoses; Naphthalenes; Sequence Analysis, DNA; Terbinafine; Triazoles; Tubulin

During a 3-year surveillance program (2004 to 2007) in Monterrey, Mexico, 398 isolates of Candida spp. were collected from five hospitals. We established the species distribution and in vitro susceptibilities of these isolates. The species included 127 Candida albicans strains, 151 C. parapsilosis strains, 59 C. tropicalis strains, 32 C. glabrata strains, 11 C. krusei strains, 5 C. guilliermondii strains, 4 C. famata strains, 2 C. utilis strains, 2 C. zeylanoides strains, 2 C. rugosa strains, 2 C. lusitaniae strains, and 1 C. boidinii strain. The species distribution differed with the age of the patients. The proportion of candidemias caused by C. parapsilosis was higher among infants 45 years old). MICs were calculated following the criteria of the Clinical Laboratory Standards Institute reference broth macrodilution method. Overall, C. albicans, C. parapsilosis, and C. tropicalis isolates were susceptible to fluconazole and amphotericin B. However, 31.3% of C. glabrata isolates were resistant to fluconazole (MIC >or= 64 microg/ml), 43.3% were resistant to itraconazole (MIC >or= 1 microg/ml), and 12.5% displayed resistance to amphotericin B (MIC >or= 2 microg/ml). Newer triazoles, namely, voriconazole, posaconazole, and ravuconazole, had a notable in vitro activity against all Candida species tested. Also, caspofungin was active against Candida sp. isolates (MIC(90)

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Candida; Candida albicans; Candida glabrata; Candida tropicalis; Candidiasis; Caspofungin; Child; Child, Preschool; Echinocandins; Female; Fluconazole; Humans; Infant; Infant, Newborn; Itraconazole; Lipopeptides; Male; Mexico; Microbial Sensitivity Tests; Middle Aged; Pyrimidines; Thiazoles; Triazoles; Voriconazole; Young Adult

Eighty-four isolates belonging to eight species that constitute the Pseudallescheria boydii complex were tested against 11 antifungal agents by using the microdilution method. There were significant differences among the species, with Scedosporium aurantiacum being the most resistant. In general, voriconazole was the most active drug, followed by posaconazole.

Topics: Amphotericin B; Antifungal Agents; Candida; Drug Resistance, Fungal; Echinocandins; Fluconazole; Flucytosine; Humans; Itraconazole; Ketoconazole; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Naphthalenes; Peptides, Cyclic; Pseudallescheria; Pyrimidines; Quality Control; Quinazolines; Scedosporium; Terbinafine; Thiazoles; Triazoles; Voriconazole

Azole resistance in Aspergillus spp. is unusual. We report a patient who received long-term treatment with itraconazole and voriconazole for bilateral chronic cavitary aspergillosis with aspergillomas whose isolates of Aspergillus fumigatus developed simultaneous resistance to itraconazole and voriconazole. A novel mutation (G138C) in the target gene (cyp51A) encoding 14alpha-demethylase was detected. The patient had some response to intravenous caspofungin, which he received six times weekly, without the development of resistance over 9 months.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Caspofungin; Cytochrome P-450 Enzyme System; Drug Resistance, Multiple, Fungal; Echinocandins; Fungal Proteins; Humans; Itraconazole; Lipopeptides; Lung Diseases, Fungal; Male; Microbial Sensitivity Tests; Middle Aged; Mutation, Missense; Peptides, Cyclic; Pyrimidines; Thiazoles; Triazoles; Voriconazole

The in vitro activities of two new triazole antifungal agents with broad-spectrum antifungal activity, posaconazole and ravuconazole, were compared with those of three well-established antifungal agents, terbinafine, itraconazole and fluconazole, against 184 clinical isolates. These included 129 dermatophyte isolates (twelve species), 25 yeast isolates (five species) and 28 non-dermatophyte isolates (nine species). In vitro testing was conducted using microdilution plates with RPMI 1640 and National Committee for Clinical Laboratory Standards (NCCLS) guidelines (M27-38P) were followed, except for the preparation of the dermatophyte inoculum. Both posaconazole and ravuconazole showed similar broad-spectrum activity against dermatophyte, yeast and non-dermatophyte species. Mean inhibitory concentrations (MIC) at which 90% [MIC90] of the isolates were inhibited by posaconazole and ravuconazole were 0.25 and 0.5 microg/ml for dermatophytes, 0.5 and 0.25 microg/ml for yeasts, and >4 and 8 microg/ml for non-dermatophytes. The MIC ranges against Trichophyton (six species), Microsporum (five species) and Epidermophyton flocossum were: posaconazole (0.007-1.0/0.007-0.25/0.007-1.0 microg/ml), ravuconazole (0.015-8.0/0.015-1.0/0.015-1.0 microg/ml), itraconazole (0.015- >8.0/0.015-0.5/ 0.015-8.0 microg/ml), fluconazole (0.125- >64.0/4.0 >64.0/0.5-64.0 microg/ml) and terbinafine (0.003 >2.0/0.007-2.0/0.007 >2.0 microg/ml). Overall ranking of the antifungal activity of the five antifungal agents was: terbinafine > posaconazole > ravuconazole > itraconazole > fluconazole, for dermatophytes; ravuconazole > posaconazole > itraconazole > fluconazole > terbinafine, against yeasts; and posaconazole > ravuconazole > terbinafine > itraconazole > fluconazole, for non-dermatophytes.

Topics: Antifungal Agents; Arthrodermataceae; Fluconazole; Fungi; Humans; Itraconazole; Microbial Sensitivity Tests; Mycoses; Naphthalenes; Terbinafine; Thiazoles; Triazoles; Yeasts

The in vitro activities of three new triazoles were determined and compared to those of itraconazole and fluconazole against 306 clinical isolates of Blastomyces dermatitidis, Cladophialophora carrionii, Coccidioides immitis, Fonsecaea pedrosoi, Fusarium spp., Histoplasma capsulatum, Paecilomyces lilacinus, Pseudallescheria boydii and Sporothrix schenckii. Minimum inhibitory concentrations (MIC) were determined by a broth macrodilution method of the National Committee for Clinical Laboratory Standards M38-A procedure. Itraconazole (geometric mean MIC, 0.16-0.65 microg/ml), voriconazole (geometric mean MIC, 0.18-1.44 microg/ml), ravuconazole (geometric mean MIC, 0.18-1.09 microg/ml), and posaconazole (geometric mean MIC, 0.18-1.38 microg/ml), had relatively uniform values showing potent in vitro inhibitory activity against B. dermatitidis, C. carrionii, C. immitis, F. pedrosoi, H. capsulatum, and S. schenckii. The in vitro activity was variable with strains of P. boydii, P. lilacinus and Fusarium spp.

Topics: Antifungal Agents; Fungi; Humans; Microbial Sensitivity Tests; Mycoses; Pyrimidines; Species Specificity; Thiazoles; Triazoles; Voriconazole

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anidulafungin; Animals; Antifungal Agents; Caspofungin; Child; Child, Preschool; Clinical Trials as Topic; Echinocandins; Fungal Proteins; Humans; Infant; Infant, Newborn; Lipopeptides; Lipoproteins; Micafungin; Middle Aged; Mycoses; Peptides, Cyclic; Pyrimidines; Thiazoles; Treatment Outcome; Triazoles; Voriconazole

A commercially prepared dried colorimetric microdilution panel (Sensititre YeastOne, TREK Diagnostic Systems, Cleveland, Ohio) was compared in three different laboratories with the National Committee for Clinical Laboratory Standards (NCCLS) reference microdilution method by testing two quality control strains and 300 clinical isolates of Candida spp. against fluconazole, voriconazole, posaconazole, and ravuconazole. Reference MIC endpoints were established after 48 h of incubation and YeastOne colorimetric endpoints were established after 24 h of incubation. YeastOne endpoints were determined to be the lowest concentration at which the color in the well changed from red (indicating growth) to purple (indicating growth inhibition) or blue (indicating no growth). Excellent agreement (within two dilutions) between the reference and colorimetric MICs was observed. Overall agreement was 95.4%. Agreement ranged from 92.3% with posaconazole to 98.0% with fluconazole. The YeastOne colorimetric method appears to be comparable to the NCCLS reference method for testing the susceptibility of Candida spp to the new triazoles voriconazole, posaconazole, and ravuconazole.

Topics: Antifungal Agents; Candida; Candidiasis; Humans; Microbial Sensitivity Tests; Pyrimidines; Reagent Kits, Diagnostic; Thiazoles; Triazoles; Voriconazole

We examined the in vitro activity of caspofungin, posaconazole, voriconazole, ravuconazole, itraconazole, and amphotericin B against 448 recent clinical mold isolates. The endpoint for reading caspofungin was the minimum effective concentration (MEC). Among the triazoles, posaconazole was most active, inhibiting 95% of isolates at 95% of Aspergillus spp. at

Topics: Amphotericin B; Anti-Bacterial Agents; Aspergillus; Caspofungin; Echinocandins; Fungi; Humans; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Mycoses; Penicillium; Peptides; Peptides, Cyclic; Pyrimidines; Thiazoles; Triazoles; Voriconazole

Posaconazole, ravuconazole, and voriconazole are new triazole derivatives that possess potent, broad-spectrum antifungal activity. We evaluated the in vitro activity of these investigational triazoles compared with that of itraconazole and amphotericin B against 239 clinical isolates of filamentous fungi from the SENTRY Program, including Aspergillus spp. (198 isolates), Fusarium spp. (7 isolates), Penicillium spp. (19 isolates), Rhizopus spp. (4 isolates), Mucor spp. (2 isolates), and miscellaneous species (9 isolates). The isolates were obtained from 16 different medical centers in the United States and Canada between January and December 2000. In vitro susceptibility testing was performed using the microdilution broth method outlined in the National Committee for Clinical Laboratory Standards M38-P document. Overall, posaconazole was the most active compound, inhibiting 94% of isolates at a MIC of < or = 1 microg/ml, followed by voriconazole (91%), amphotericin B (89%), ravuconazole (88%), and itraconazole (70%). All three new triazoles demonstrated excellent activity (MIC, < or = 1 microg/ml) against Aspergillus spp. (114 Aspergillus fumigatus, 22 Aspergillus niger, 13 Aspergillus flavus, 9 Aspergillus versicolor, 8 Aspergillus terreus, and 32 Aspergillus spp.): posaconazole (98%), voriconazole (98%), ravuconazole (92%), amphotericin B (89%), and itraconazole (72%). None of the triazoles were active against Fusarium spp. (MIC at which 50% of the isolates tested were inhibited [MIC(50)], >8 microg/ml) or Mucor spp. (MIC(50), >8 microg/ml). Posaconazole and ravuconazole were more active than voriconazole against Rhizopus spp. (MIC(50), 1 to 2 microg/ml versus >8 microg/ml, respectively). Based on these results, all three new triazoles exhibited promising activity against Aspergillus spp. and other less commonly encountered isolates of filamentous fungi. The clinical value of these in vitro data remains to be seen, and in vitro-in vivo correlation is needed for both new and established antifungal agents. Surveillance efforts should be expanded in order to monitor the spectrum of filamentous fungal pathogens and their in vitro susceptibility as these new antifungal agents are introduced into clinical use.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Canada; Fungi; Humans; Microbial Sensitivity Tests; Mycoses; Pyrimidines; Quality Control; Thiazoles; Triazoles; United States; Voriconazole

A commercially prepared frozen broth microdilution panel (Trek Diagnostic Systems, Westlake, Ohio) was compared with a reference microdilution panel for antifungal susceptibility testing of two quality control (QC) strains and 99 clinical isolates of Candida spp. The antifungal agents tested included amphotericin B, flucytosine, fluconazole, itraconazole, posaconazole, ravuconazole, and voriconazole. Microdilution testing was performed according to NCCLS recommendations. MIC endpoints were read visually after 48 h of incubation and were assessed independently for each microdilution panel. The MICs for the QC strains were within published limits for both the reference and Trek microdilution panels. Discrepancies among MIC endpoints of no more than 2 dilutions were used to calculate the percent agreement. Acceptable levels of agreement between the Trek and reference panels were observed for all antifungal agents tested against the 99 clinical isolates. The overall agreement for each antifungal agent ranged from 96% for ravuconazole to 100% for amphotericin B. The Trek microdilution panel appears to be a viable alternative to frozen microdilution panels prepared in-house.

Topics: Antifungal Agents; Candida; Freezing; Humans; Microbial Sensitivity Tests; Pyrimidines; Thiazoles; Triazoles; Voriconazole

The in vitro activities of voriconazole, posaconazole, ravuconazole and micafungin were compared with those of fluconazole, itraconazole, ketoconazole, flucytosine and amphotericin B against 164 candidaemia isolates recovered from cancer patients in two Canadian centres. The MIC(50) results for ravuconazole, voriconazole, posaconazole and micafungin were 0.01, 0.03, 0.12 and 0.25 mg/L, respectively. The new antifungal agents showed substantial activity against isolates demonstrating in vitro resistance to fluconazole and itraconazole. These results suggest that the newer antifungal agents possess promising activity against invasive Candida isolates, particularly against those with reduced susceptibility to fluconazole and itraconazole.

Topics: Antifungal Agents; Blood; Candida; Candidiasis; Echinocandins; Humans; In Vitro Techniques; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Neoplasms; Peptides, Cyclic; Pyrimidines; Thiazoles; Triazoles; Voriconazole

In order to develop new approaches to the treatment of the severe and usually fatal infections caused by Scedosporium spp., the in vitro antifungal activities of four novel triazoles (posaconazole, ravuconazole, voriconazole, and UR-9825) and some current antifungals (amphotericin B, ketoconazole, itraconazole, and nystatin) were determined. The latter group was clearly ineffective against the two species tested. The four new antifungals showed activity against Scedosporium apiospermum, and UR-9825 and voriconazole were active against S. prolificans.

Topics: Antifungal Agents; Humans; Microbial Sensitivity Tests; Pyrimidines; Quinazolines; Scedosporium; Thiazoles; Triazoles; Voriconazole

Candida dubliniensis is a newly recognized fungal pathogen causing mucosal disease in AIDS patients. Although preliminary studies indicate that most strains of C. dubliniensis are susceptible to established antifungal agents, fluconazole-resistant strains have been detected. Furthermore, fluconazole-resistant strains are easily derived in vitro, and these strains exhibit increased expression of multidrug resistance transporters, especially MDR1. Because of the potential for the development of resistant strains of C. dubliniensis, it is prudent to explore the in vitro activities of several of the newer triazole and echinocandin antifungals against isolates of C. dubliniensis. In this study we tested 71 isolates of C. dubliniensis against the triazoles BMS-207147, Sch 56592, and voriconazole and a representative of the echinocandin class of antifungal agents, MK-0991. We compared the activities of these agents with those of the established antifungal agents fluconazole, itraconazole, amphotericin B, and 5-fluorocytosine (5FC) by using National Committee for Clinical Laboratory Standards microdilution reference methods. Our findings indicate that the vast majority of clinical isolates of C. dubliniensis are highly susceptible to both new and established antifungal agents. Strains with decreased susceptibilities to fluconazole remained susceptible to the investigational agents as well as to amphotericin B and 5FC. The increased potencies of the new triazole and echinocandin antifungal agents may provide effective therapeutic options for the treatment of infections due to C. dubliniensis.

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Candida; Candidiasis; Caspofungin; Echinocandins; Fluconazole; Flucytosine; Humans; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Peptides; Peptides, Cyclic; Pyrimidines; Thiazoles; Triazoles; Voriconazole

BMS-207147, Sch 56592, and voriconazole are three new investigational triazoles with broad-spectrum antifungal activity. The in vitro activities of these three agents were compared with those of itraconazole and fluconazole against 1,300 bloodstream isolates of Candida species obtained from over 50 different medical centers in the United States. The MICs of all of the antifungal drugs were determined by broth microdilution tests performed according to the National Committee for Clinical Laboratory Standards method using RPMI 1640 as a test medium. BMS-207147, Sch 56592, and voriconazole were all quite active against all Candida sp. isolates (MICs for 90% of the isolates tested [MIC90s], 0.5, 1.0, and 0.5 microgram/ml, respectively). Candida albicans was the most susceptible species (MIC90s, 0.03, 0.06, and 0.06 microgram/ml, respectively), and C. glabrata was the least susceptible (MIC90s, 4. 0, 4.0, and 2.0 microgram/ml, respectively). BMS-207147, Sch 56592, and voriconazole were all more active than itraconazole and fluconazole against C. albicans, C. parapsilosis, C. tropicalis, and C. krusei. There existed a clear rank order of in vitro activity of the five azoles examined in this study when they were tested versus C. glabrata: voriconazole > BMS-207147 = Sch 56592 = itraconazole > fluconazole (MIC90s, 2.0, 4.0, 4.0, 4.0, and 64 microgram/ml, respectively). For isolates of Candida spp. with decreased susceptibility to both itraconazole and fluconazole, the MICs of BMS-207147, Sch 56592, and voriconazole were also elevated. These results suggest that BMS-207147, Sch 56592, and voriconazole all possess promising antifungal activity and that further in vitro and in vivo investigations are warranted to establish the clinical value of this improved potency.

Topics: Antifungal Agents; Candida; Candidiasis; Humans; Microbial Sensitivity Tests; Pyrimidines; Thiazoles; Triazoles; Voriconazole