In vitro antifungal activity of BMS-207147 and itraconazole against yeast strains that are non-susceptible to fluconazole

Fung‐Tomc, Joan; White, Theodore C.; Minassian, Beatrice; Huczko, E; Bonner, Daniel P.

doi:10.1016/s0732-8893(99)00063-2

Cited by 39 publications

(44 citation statements)

References 16 publications

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“…Species such as Scedosporium prolificans, Fusarium spp., and Scopulariopsis spp. were resistant to the triazole.Ravuconazole is an extended-spectrum investigational triazole agent that is highly active in vitro against Candida spp., Cryptococcus neoformans, and other yeast species (9,12,20,24,28), even against the majority of fluconazole-resistant isolates of yeasts (4,10,22). Ravuconazole also has shown the capability of inhibiting in vitro growth of Aspergillus spp.…”

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In Vitro Activity of Ravuconazole against 923 Clinical Isolates of Nondermatophyte Filamentous Fungi

Cuenca‐Estrella

Gómez-López

Mellado

et al. 2005

Antimicrob Agents Chemother

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The in vitro activities of ravuconazole against 575 clinical strains of Aspergillus spp. and 348 nondermatophyte non-Aspergillus spp. were analyzed. Ravuconazole was active against Aspergillus spp., other hyaline filamentous fungi, black molds, and some Mucorales. Species such as Scedosporium prolificans, Fusarium spp., and Scopulariopsis spp. were resistant to the triazole.Ravuconazole is an extended-spectrum investigational triazole agent that is highly active in vitro against Candida spp., Cryptococcus neoformans, and other yeast species (9,12,20,24,28), even against the majority of fluconazole-resistant isolates of yeasts (4,10,22). Ravuconazole also has shown the capability of inhibiting in vitro growth of Aspergillus spp. (7,8,18,23,27). In addition, reports from studies including a limited number of clinical strains have indicated that ravuconazole has an inhibitory effect against most of the isolates belonging to species such as Penicillium spp., Paecilomyces spp., Scedosporium apiospermum, and dermatophytes (2,7,13,17,26). However, strains of other species are largely resistant to ravuconazole in vitro, as has been reported for Fusarium, Scedosporium prolificans, and several species of Mucorales (2, 7, 26).We have analyzed the activities of ravuconazole against a collection of 923 clinical isolates of filamentous fungi. A total of 575 strains of Aspergillus spp. and 348 nondermatophyte non-Aspergillus spp. were included, representing the largest panel of non-Aspergillus molds against which ravuconazole has been tested up to now.The strains were recovered from 83 Spanish hospitals through a period of 5 years, from 2000 to 2004. The isolates were obtained from respiratory tract specimens (571/923; 61.9%), skin samples (114/923; 12.4%), and other locations (238/923; 25.7%). Aspergillus fumigatus ATCC 204305 and Aspergillus flavus ATCC 204304 were included as control isolates in each set of experiments.The following antifungal agents were used in the study: Ravuconazole (Bristol-Myers Squibb, Princeton, N.J.), amphotericin B (Sigma Aldrich Quimica S.A., Madrid, Spain), itraconazole (Janssen S.A., Madrid, Spain), and voriconazole (Pfizer S.A., Madrid, Spain).A broth microdilution test was performed by following the Clinical Laboratory Standards Institute (CLSI [formerly NCCLS]) reference method (19), with minor modifications. The modifications included the use of RPMI 1640 with Lglutamine buffered to pH 7 with 0.165 M morpholinepropanesulfonic acid and 10 M NaOH, supplemented with 18 g of glucose per liter (RPMI-2% glucose; OXOID, Madrid, Spain) and an inoculum size of (1 to 5) ϫ 10 5 CFU/ml (6, 11, 14). Inoculum suspensions were prepared from fresh, mature (3-to 5-day-old) cultures following a methodology reported previously (25). The plates were incubated at 35°C for 48 h in a humid atmosphere. Visual readings were performed with the help of a mirror. MICs were defined as the lowest concentrations of the antifungal agent that completely inhibited fungal growth.Strains were classified as 64 distinct species...

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In Vitro Activity of Ravuconazole against 923 Clinical Isolates of Nondermatophyte Filamentous Fungi

Cuenca‐Estrella

Gómez-López

Mellado

et al. 2005

Antimicrob Agents Chemother

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“…Most of the azoles under development have a broader spectrum but cannot be administered parenterally because of low water-solubility. [7][8][9][10] There have been some efforts to overcome this problem by using a prodrug approach. [11][12][13][14] Previously, we identified CS-758 [15][16][17] which has a broad antifungal spectrum covering Aspergillus spp., FLCZ-resistant Candida spp.…”

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Design, Synthesis and Antifungal Activity of the Novel Water-Soluble Prodrug of Antifungal Triazole CS-758

Kagoshima

Mori

Suzuki

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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CS-758 was selected as a candidate for clinical trials, but since its water-solubility was insufficient for an injectable formulation, phosphoryl ester prodrugs were designed. In this study, the synthesis and evaluation of these injectable prodrugs are described. Phosphoryl ester 17h was soluble in water, and was stable in both water and in a solid state. 17h was converted to CS-758 in human liver microsome and was also converted to CS-758 in rats after intravenous (i.v.) administration with good conversion speed and efficiency. 17h (i.v.) reduced the viable cell counts in kidneys in a murine hematogenous Candida albicans infection model and in lungs in a murine pulmonary Aspergillus fumigatus infection model, wherein the effects were comparable to or slightly superior to that of CS-758 (per os).

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“…In vitro studies have demonstrated potent activity of ravuconazole against Candida albicans, C. dubliniensis (including fluconazole-and itraconazole-resistant isolates), C. tropicalis, C. parapsilosis, C. krusei, and Cryptococcus neoformans (16,36,37,49). Additional studies have demonstrated that ravuconazole is active in vitro against clinical isolates of filamentous fungi, including Aspergillus spp., Fusarium spp., Scedosporium apiospermum, and Trichosporon spp.…”

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Efficacy, Safety, and Plasma Pharmacokinetics of Escalating Dosages of Intravenously Administered Ravuconazole Lysine Phosphoester for Treatment of Experimental Pulmonary Aspergillosis in Persistently Neutropenic Rabbits

Petraitienė

Petraitis

Lyman

et al. 2004

Antimicrob Agents Chemother

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Ravuconazole is a new antifungal triazole with broad-spectrum activity and a long half-life in plasma. We studied the antifungal efficacy, safety, and pharmacokinetics of ravuconazole lysine phosphoester in escalating dosages for the treatment of invasive pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Treatment groups consisted of rabbits treated with ravuconazole at 2.5 (RVC2.5), 5 (RVC5), and 10 (RVC10) mg/kg of body weight/day, rabbits treated with amphotericin B (AMB) at 1 mg/kg/day, or untreated controls. There was a dose-dependent reduction of pulmonary residual fungal burden (CFU per gram) in RVC5-, RVC10-, and AMB-treated rabbits in comparison to untreated controls (P < 0.01, P < 0.001, and P < 0.01, respectively). These findings correlated with progressive galactomannan antigenemia in untreated controls and the RVC2.5-treated rabbits, a lower galactomannan index (GMI) in RVC5-and RVC10-treated rabbits, and a similarly low GMI in AMB-treated rabbits (P < 0.01). Rabbits treated with RVC5, RVC10, and AMB also showed a reduction of organism-mediated pulmonary injury, as measured by infarct scores and lung weights, in comparison to untreated controls (P < 0.001). These results were supported by decreased pulmonary infiltrates detected by computed tomography in RVC5-and RVC10-treated rabbits in comparison to untreated controls (P < 0.05). Survival throughout the entire study was achieved in 95% of RVC5-treated rabbits (P < 0.001), 85% of RVC10-treated rabbits (P < 0.001), and 50% of AMB-treated rabbits (P < 0.05) in comparison to none of the untreated controls. Ravuconazole showed linear plasma pharmacokinetics and a large volume of distribution while maintaining concentrations in plasma above the MIC throughout the dosing interval. There was no evidence of hepatotoxicity or nephrotoxicity among ravuconazoletreated animals. Intravenously administered ravuconazole lysine phosphoester showed dose-dependent efficacy and an excellent safety profile for the treatment of invasive pulmonary aspergillosis in persistently neutropenic rabbits.

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In vitro antifungal activity of BMS-207147 and itraconazole against yeast strains that are non-susceptible to fluconazole

Cited by 39 publications

References 16 publications

In Vitro Activity of Ravuconazole against 923 Clinical Isolates of Nondermatophyte Filamentous Fungi

In Vitro Activity of Ravuconazole against 923 Clinical Isolates of Nondermatophyte Filamentous Fungi

Design, Synthesis and Antifungal Activity of the Novel Water-Soluble Prodrug of Antifungal Triazole CS-758

Efficacy, Safety, and Plasma Pharmacokinetics of Escalating Dosages of Intravenously Administered Ravuconazole Lysine Phosphoester for Treatment of Experimental Pulmonary Aspergillosis in Persistently Neutropenic Rabbits

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