In Vitro Antifungal Activities of the New Triazole UR-9825 against Clinically Important Filamentous Fungi

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We have evaluated the in vitro activity of 15 combinations of antifungal drugs (amphotericin B, itraconazole, voriconazole, albaconazole, ravuconazole, terbinafine, and micafungin) against four isolates of Paecilomyces variotii and three of P. lilacinus. The interaction of terbinafine with the four azoles was synergistic for 53% of the combinations, while the interactions of both amphotericin B and micafungin with the rest of antifungal agents were mainly indifferent.Paecilomyces species are saprophytic fungi usually recovered from soil and air which can cause the deterioration of grain, food, and paper. They can contaminate antiseptic creams and lotions of clinical use and colonize materials such as catheters and plastic implants, causing infections in immunocompetent and immunocompromised patients (4, 9). Paecilomyces variotii and P. lilacinus are the most ubiquitous species of the genus and also the most frequently involved in human infections (4,14). Endophthalmitis and endocarditis are two of the most common infections produced by P. lilacinus and P. variotii, respectively, and have a very bad prognosis (4). Amphotericin B (AMB), alone or combined with flycytosine or azoles, is the standard treatment, but a failure rate of about 40% indicates that the proper treatment has not yet been found. Hence, new treatment regimens are needed, and the combination of antifungal agents constitutes an interesting new alternative to be tested. Allylamines and especially echinocandins are new classes of antifungal agents with novel targets, which make them very interesting for combination studies (6). In recent years, numerous studies have been performed to determine the in vitro activity of combinations of the available drugs against filamentous fungi, although the genus Paecilomyces was not included in any of them (2,12).Seven clinical isolates of Paecilomyces spp. (four strains of P. variotii and three strains of P. lilacinus) were tested. The isolates were grown on potato dextrose agar plates and incubated at 30°C for 7 to 10 days. Inocula were prepared by following the NCCLS guidelines (10) and adjusted to a final concentration of 1.1 ϫ 10 4 to 3.4 ϫ 10 4 conidia/ml. Antifungal agents were obtained as pure powders. AMB (USP, Rockville, Md.), itraconazole (ITZ) (Janssen Pharmaceutica, Beerse, Belgium), voriconazole (VCZ) (Pfizer Inc., Madrid, Spain), albaconazole (ABZ) (J. Uriach & Cia., Barcelona, Spain), ravuconazole (RVZ) (Bristol-Myers Squibb Company, New Brunswick, N.J.), and terbinafine (TBF) (Novartis, Basel, Switzerland) were dissolved in dimethyl sulfoxide. Micafungin (MFG) was obtained from Fujisawa Pharmaceutical Co. Ltd. (Osaka, Japan) and was dissolved in water.The MICs of all drugs were defined as the lowest drug concentrations that produced a 100% inhibition of visible fungal growth after 48 to 72 h of incubation at 35°C. Drug interactions were assessed by a checkerboard microdilution method that also included the determination of the MIC of each drug alone in the same plate by using the parameters outli...

“…For P. lilacinus only the novel azole derivatives, and especially RVZ, were active. These results generally confirmed our earlier studies (1,3) and those of other authors (7).…”

supporting

confidence: 83%

In Vitro Interactions of Approved and Novel Drugs against Paecilomyces spp

Ortoneda¹,

Capilla²,

Pastor³

et al. 2004

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“…The antifungal activity of AMB obtained here agrees with those found by other investigators (4,11,13). In a previous study we reported AMB MICs similar to those obtained here (MIC 90 , 9.23 g/ml at 72 h of incubation), even though the results were generated by the macrodilution method.…”

Section: Discussionsupporting

confidence: 83%

In Vitro Activities of New Antifungal Agents against Chaetomium spp. and Inoculum Standardization

Serena

Ortoneda

Capilla

et al. 2003

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Chaetomium is an unusual etiological agent of human infections, but the mortality rate among immunocompromised patients is considerably greater than that among nonimmunocompromised individuals. We investigated the in vitro antifungal susceptibilities to novel antifungal agents of 19 strains belonging to three species of Chaetomium which have been involved in human infections, i.e., Chaetomium globosum, C. atrobrunneum, and C. nigricolor, and one strain of the closely related species Achaetomium strumarium. A modification of the NCCLS reference microdilution method (M38-A) was used to evaluate the in vitro activities of ravuconazole, voriconazole, albaconazole, and micafungin. Micafungin was not active at all, while the geometric mean MICs and minimum effective concentrations of the three triazoles were less than 0.5 and 0.4 g/ml, respectively.Several species of the ascomycete genus Chaetomium are able to cause human infections, and these mainly affect the nails or skin (5). However, disseminated infections have also been reported, especially in neutropenic patients (11). Despite antifungal treatments with amphotericin B (AMB) alone or in combination with itraconazole, the mortality rate among patients with severe infections caused by Chaetomium is high (M. A. Barron, D. A. Sutton, R. Veve, J. Guarro, M. Rinaldi, E. Thompson, P. J. Cagnoni, and N. E. Madinger, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. 870, 2002). The most prevalent clinical species is Chaetomium globosum, although other species have also been reported (11). Clinical and in vitro data on the activities of antifungal drugs against the different species of Chaetomium are scarce. In previous studies, using broth macro-and microdilution methods, we demonstrated the inhibitory activities of miconazole, ketoconazole, and itraconazole in vitro (11,17). However, the susceptibility of Chaetomium to the novel antifungal drugs is practically unknown.In this work we have evaluated the in vitro activities of the new triazoles albaconazole (ABC), voriconazole (VRC), and ravuconazole (RVC) and the echinocandin micafungin (MFG) against a representative number of strains of Chaetomium species of clinical interest and one strain of Achaetomium strumarium, which has also been involved in human infections. We followed the guidelines of NCCLS reference method M38-A for antifungal susceptibility testing of molds (14). However, since this reference method does not apply to fungi that reproduce by ascospores instead of conidia, we have made a few modifications to the type and the size of the inoculum and the incubation conditions. MATERIALS AND METHODSIsolates. Nineteen isolates of Chaetomium spp. (11 isolates of C. globosum, 7 isolates of C. atrobrunneum, 1 isolate of C. nigricolor) and 1 isolate of A. strumarium were tested; all of them were from clinical sources. The isolates were stored on oatmeal agar (OA; oatmeal, 30 g; agar, 20 g; tap water, 1 liter) slants covered with paraffin oil, subcultured on OA plates, and incubated at 30°C for 15 t...

“…The new triazole albaconazole (ABC) showed good in vitro activity against this fungus in a recent study which tested 30 strains (5). This drug has also shown good in vitro activity against dermatophytes, Aspergillus, Paecilomyces, and Candida species, among others (4,8,19). The concentrations of this drug achieved in plasma of mice are very low, and its half-life is short; however, its pharmacokinetics and bioavailability are excellent in rabbits (1).…”

mentioning

confidence: 99%

Efficacy of Albaconazole (UR-9825) in Treatment of DisseminatedScedosporium prolificansInfection in Rabbits

Capilla¹,

Yustes²,

Mayayo

et al. 2003

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There are no effective therapeutics for treating invasive Scedosporium prolificans infections. Doses of 15, 25, and 50 mg/kg of body weight/day for the new triazole albaconazole (ABC) were evaluated in an immunocompetent rabbit model of systemic infection with this mold. Treatments were begun 1 day after challenge and given for 10 days. ABC at any dose was more effective than amphotericin B (AMB) at 0.8 mg/kg/day at clearing S. prolificans from tissue (P < 0.007). The percentages of survival at 25 mg of ABC/kg/day were similar to those obtained with AMB. Rabbits showed 100% survival when they were treated with 50 mg of ABC per kg (P < 0.0001 versus control group), and only this dosage was able to reduce tissue burden significantly in the five organs studied, i.e., spleen, kidneys, liver, lungs, and brain.Scedosporium prolificans is an emerging filamentous fungus that infects both immunosuppressed and healthy patients, and it is the most common agent of disseminated phaeohyphomycosis (2,11,14,15,20). The infection is probably mostly acquired by inhalation of conidia and can take a wide variety of forms. Disseminated infection is associated mainly with patients with underlying blood malignancies and is usually fatal. The infection is generally treated with amphotericin B (AMB) and occasionally with other drugs, although the outcome is not often successful (2,9,15,20). Several in vitro studies have demonstrated that S. prolificans is generally resistant to the antifungal agents available, and this correlates with the poor clinical response (5, 7). In a previous paper, we demonstrated that high doses of liposomal amphotericin B (10 mg/kg of body weight/day) combined with granulocyte colony-stimulating factor were moderately effective in the treatment of murine scedosporiosis (18). However, further studies are required to determine whether more appropriate dosages of the drug and more suitable strategies that combine it with granulocyte colony-stimulating factor or other lymphokines provide better results. Another alternative, which is practically unexplored, is to use a therapy combining two antifungal agents. In vitro studies have demonstrated that itraconazole combined with terbinafine has a synergic effect against clinical isolates of this fungus (16). This is a line of investigation that deserves to be developed, although the rapid clearance of both drugs in mice makes it necessary to use other animal models for testing this combination. In spite of these promising approaches, alternative treatments for these severe and increasingly frequent mycoses still need to be investigated. The new triazole albaconazole (ABC) showed good in vitro activity against this fungus in a recent study which tested 30 strains (5). This drug has also shown good in vitro activity against dermatophytes, Aspergillus, Paecilomyces, and Candida species, among others (4,8,19). The concentrations of this drug achieved in plasma of mice are very low, and its half-life is short; however, its pharmacokinetics and bioavailability are excellent ...