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In vitro activities of BMS-207147 against over 600 contemporary clinical bloodstream isolates of Candida species from the SENTRY Antimicrobial Surveillance Program in North America and Latin America.

Diekema DJ, Pfaller MA, Messer SA, Houston A, Hollis RJ, Doern GV, Jones RN.

Medical Microbiology Division, Department of Pathology, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA. daniel-diekema uiowa.edu

We compared the in vitro activity of BMS-207147, an investigational triazole, with those of itraconazole and fluconazole against 613 clinical bloodstream isolates of Candida spp. collected from SENTRY participating hospitals during 1997 and 1998. Overall, BMS-207147 was the most active azole against all Candida spp. While both BMS-207147 and itraconazole displayed a stepwise decrease in activity against isolates for which the fluconazole MICs were elevated, BMS-207147 had two- to fourfold greater activity than itraconazole both against Candida spp. that were dose-dependently fluconazole susceptible and against those that were fluconazole resistant.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10471571&dopt=Abstract fluconazole Diflucan



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In-vitro activity of dicationic aromatic compounds and fluconazole against Cryptococcus neoformans and Candida spp.

Del Poeta M, Bixel AS, Barchiesi F, Tidwell RR, Boykin D, Scalise G, Perfect JR.

Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.

We investigated the in-vitro activity of three selected dicationic aromatic compounds for nine clinical isolates of Cryptococcus neoformans and 93 clinical isolates of Candida spp., representing 12 different species, using a broth macrodilution method following NCCLS recommendations. All the clinical isolates were also tested for fluconazole susceptibility. The in-vitro data demonstrate that compounds 39 and 57 have excellent in-vitro activity for all tested strains (MIC 0.19-1.56 mg/L) except Candida pelliculosa. Moreover, compound 39 showed excellent in-vitro fungicidal activity against Candida krusei, Candida glabrata, Candida lusitaniae and Cryptococcus neoformans with MFCs in the range 0.39-6.25 mg/L. Both compounds 39 and 57 showed excellent in-vitro activity against fluconazole-resistant Candida albicans isolates, including a C. albicans strain that contains all known fluconazole-resistant mechanisms. Comparing MIC data from compounds 21, 39 and 57 with fluconazole, we found a statistically significant difference only with compound 39 (P = 0.043). However, comparing MFC data from compounds 21, 39 and 57 with fluconazole, we found statistically significant differences with all three compounds (P < 0.00001). These data indicate the potential antifungal breadth of two bis-benzimidazoles (compounds 39 and 57) as antifungal agents against yeasts. If it can be determined that compounds 39 and 57 are effective and non-toxic in vivo, the prospect of these compounds as clinically useful antifungal agents will be enhanced.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10473229&dopt=Abstract fluconazole Diflucan



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In-vitro comparative activity of UR-9825, itraconazole and fluconazole against clinical isolates of Candida spp.

Ramos G, Cuenca-Estrella M, Monzon A, Rodriguez-Tudela JL.

Unidad de Micologia, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.

UR-9825 is a new broad-spectrum triazole antifungal agent with a good pharmacokinetic profile and excellent bioavailability. It shows high in-vitro activity and efficacy in models of systemic candidosis in rats and rabbits, comparing favourably with fluconazole. The purpose of this study was to evaluate the in-vitro activity of UR-9825 and to compare it with that of fluconazole and itraconazole against 283 clinical isolates of Candida spp. UR-9825 was more potent against Candida spp. than both fluconazole and itraconazole, even against some Candida albicans and Candida krusei isolates with decreased susceptibility to fluconazole (MIC 16 mg/L).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10473237&dopt=Abstract fluconazole Diflucan



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Low levels of antigenic variability in fluconazole-susceptible and -resistant Candida albicans isolates from human immunodeficiency virus-infected patients with oropharyngeal candidiasis.

Lopez-Ribot JL, McAtee RK, Kirkpatrick WR, La Valle R, Patterson TF.

Department of Medicine, Division of Infectious Diseases, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284-7881, USA. ribot uthscsa.edu

Three serial isolates of Candida albicans were obtained by direct swab or by oral saline rinses from each of five human immunodeficiency virus-infected patients with recurrent oropharyngeal candidiasis. Genotyping techniques confirmed the presence of a persistent strain in multiple episodes from the same patient, which was different from the strains isolated from other patients. Fluconazole susceptibility was determined by both an agar dilution method and the National Committee for Clinical Laboratory Standards macrobroth procedure. In four of these patients the strains developed fluconazole resistance, and in one patient the strain remained susceptible. The different isolates were propagated as yeast cells on a synthetic medium, and their cell wall proteinaceous components were extracted by treatment with beta-mercaptoethanol. Protein and mannoprotein components present in the extracts were analyzed by electrophoresis, immunoblotting, and lectin-blotting techniques. The analysis showed a similar composition, with only minor qualitative and quantitative differences in the polypeptidic and antigenic patterns associated with the cell wall extracts from serial isolates from the same patient, as well as those from different strains isolated from different patients. Use of monospecific antibodies generated against two immunodominant antigens during candidiasis (enolase and the 58-kDa fibrinogen-binding mannoprotein) demonstrated their expression in all isolates tested. Overall, the antigenic makeup of C. albicans strains remained constant during the course of infection and was not affected by development of fluconazole resistance. In contrast to previous reports, the low degree of antigenic variability observed in this study may be due to the fact that the isolates were obtained from a highly homogeneous population of patients and to the uniformity in techniques used for the isolation, storage, and culture of the different strains, as well as extraction methodologies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10473514&dopt=Abstract fluconazole Diflucan



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Alternatives to amphotericin B for Candida rugosa infection.

Hernandez S, Gonzalez GM, McCarthy DI, Colombo AL, Najvar LK, Bocanegera R, Graybill JR.

Department of Medicine, Division of Infectious Diseases, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA. Hernandezs uthscsa.edu

OBJECTIVE: Amphotericin B failure is frequently seen in patients with candidaemia caused by Candida rugosa. We evaluated amphotericin B, fluconazole, posaconazole and voriconazole as alternative treatments against infection in mice with two isolates of C. rugosa. METHODS: Neutropenic mice were inoculated intravenously with C. rugosa. Amphotericin B, fluconazole, posaconazole and voriconazole were administered for 7 days after infection. Efficacy of the antifungal treatment was assessed by survival and tissue burden of C. rugosa. RESULTS: All of the four drugs significantly prolonged survival over controls. With both isolates, kidney counts were reduced significantly below controls for amphotericin B, fluconazole and posaconazole. However, voriconazole was less effective than the other antifungals. CONCLUSION: Despite poor clinical response to amphotericin B, in vivo data indicate that amphotericin B increases organ clearance and survival over untreated controls. However, although voriconazole improved survival over controls, increased tissue clearance was not seen. This discrepancy may be caused by rapid clearance of voriconazole in mice. These studies suggest fluconazole, posaconazole or voriconazole may be useful alternatives to amphotericin B in therapy of C. rugosa infection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15215225&dopt=Abstract fluconazole Diflucan



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Quantitation of ergosterol content: novel method for determination of fluconazole susceptibility of Candida albicans.

Arthington-Skaggs BA, Jradi H, Desai T, Morrison CJ.

Mycotic Diseases Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA.

MIC end points for the most commonly prescribed azole antifungal drug, fluconazole, can be difficult to determine because its fungistatic nature can lead to excessive "trailing" of growth during susceptibility testing by National Committee for Clinical Laboratory Standards broth macrodilution and microdilution methods. To overcome this ambiguity, and because fluconazole acts by inhibiting ergosterol biosynthesis, we developed a novel method to differentiate fluconazole-susceptible from fluconazole-resistant isolates by quantitating ergosterol production in cells grown in 0, 1, 4, 16, or 64 microg of fluconazole per ml. Ergosterol was isolated from whole yeast cells by saponification, followed by extraction of nonsaponifiable lipids with heptane. Ergosterol was identified by its unique spectrophotometric absorbance profile between 240 and 300 nm. We used this sterol quantitation method (SQM) to test 38 isolates with broth microdilution end points of </=8 microg/ml (susceptible), 16 to 32 microg/ml (susceptible dose-dependent [SDD]), or >/=64 microg/ml (resistant) and 10 isolates with trailing end points by the broth microdilution method. No significant differences in mean ergosterol content were observed between any of the isolates grown in the absence of fluconazole. However, 18 susceptible isolates showed a mean reduction in ergosterol content of 72% after exposure to 1 microg of fluconazole/ml, an 84% reduction after exposure to 4 microg/ml, and 95 and 100% reductions after exposure to 16 and 64 microg of fluconazole/ml, respectively. Ten SDD isolates showed mean ergosterol reductions of 38, 57, 73, and 99% after exposure to 1, 4, 16, and 64 microg of fluconazole/ml, respectively. In contrast, 10 resistant isolates showed mean reductions in ergosterol content of only 25, 38, 53, and 84% after exposure to the same concentrations of fluconazole. The MIC of fluconazole, by using the SQM, was defined as the lowest concentration of the drug which resulted in 80% or greater inhibition of overall mean ergosterol biosynthesis compared to that in the drug-free control. Of 38 isolates which gave clear end points by the broth microdilution method, the SQM MIC was within 2 dilutions of the broth microdilution MIC for 33 (87%). The SQM also discriminated between resistant and highly resistant isolates and was particularly useful for discerning the fluconazole susceptibilities of 10 additional isolates which gave equivocal end points by the broth microdilution method due to trailing growth. In contrast to the broth microdilution method, the SQM determined trailing isolates to be susceptible rather than resistant, indicating that the SQM may predict clinical outcome more accurately. The SQM may provide a means to enhance current methods of fluconazole susceptibility testing and may provide a better correlation of in vitro with in vivo results, particularly for isolates with trailing end points.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10488201&dopt=Abstract fluconazole Diflucan



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Multiple effects of green tea catechin on the antifungal activity of antimycotics against Candida albicans.

Hirasawa M, Takada K.

Department of Microbiology, Nihon University School of Dentistry at Matsudo, 2-870-1 Sakaecho-nishi, Matsudo City, Chiba 271-8587, Japan. masahira mascat.nihon-u.ac.jp

OBJECTIVES: The susceptibility of Candida albicans to catechin under varying pH conditions and the synergism of the combination of catechin and antimycotics were evaluated.Method: Antifungal activity was determined by broth dilution and calculation of cfu. RESULTS: The antifungal activity of catechin was pH dependent. The concentration of epigallocatechin gallate (EGCg) causing 90% growth inhibition of tested strains of C. albicans was 2000 mg/L at pH 6.0, 500-1000 mg/L at pH 6.5 and 15.6-250 mg/L at pH 7.0. Among catechins, pyrogallol catechin showed stronger antifungal activity against C. albicans than catechol catechin. The addition of 6.25-25 or 3.12-12.5 mg/L EGCg to amphotericin B 0.125 or 0.25 mg/L (below MIC) at pH 7.0 resulted in enhancement, respectively, of the antifungal effect of amphotericin B against amphotericin B-susceptible or -resistant C. albicans. Combined treatment with 3.12-12.5 mg/L EGCg plus amphotericin B 0.5 mg/L (below MIC) markedly decreased the growth of amphotericin B-resistant C. albicans. When fluconazole-susceptible C. albicans was treated with 25-50 mg/L EGCg and fluconazole 0.125-0.25 mg/L (below MIC), its growth was inhibited by 93.0%-99.4% compared with its growth in the presence of fluconazole alone. The combined use of 12.5 mg/L EGCg and fluconazole 10-50 mg/L (below MIC) inhibited the growth of fluconazole-resistant C. albicans by 98.5%-99.7%. CONCLUSIONS: These results indicate that EGCg enhances the antifungal effect of amphotericin B or fluconazole against antimycotic-susceptible and -resistant C. albicans. Combined treatment with catechin allows the use of lower doses of antimycotics and induces multiple antifungal effects. It is hoped that this may help to avoid the side effects of antimycotics.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14688042&dopt=Abstract fluconazole Diflucan



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Serotypes of clinical cerebrospinal fluid Cryptococcus neoformans isolates from southern Taiwan and their in vitro susceptibilities to amphotericin B, fluconazole, and voriconazole.

Chang WN, Huang CR, Lei CB, Lee PY, Chien CC, Chang HW, Chang CS, Lu CH.

Department of Neurology, Chang Gung Memorial Hospital-Kaohsiung, Kaohsiung Hsien, Taiwan. cwenneng ms19.hinet.net

In this study, 34 clinical cerebrospinal fluid isolates of Cryptococcus neoformans were serotyped, and their in vitro susceptibilities to amphotericin B, fluconazole, and voriconazole were analyzed. Of these 34 isolates, serotype A was found in 29 isolates and serotype B in the other five. The voriconazole geometric mean MIC was significantly lower than the amphotericin B/antibiotic medium 3 geometric mean MIC (P < 0.0001 at both 48 and 72 h), as well as the fluconazole geometric mean MIC (P < 0.0001 at both 48 and 72 h). Of the three antifungal agents, only fluconazole, with geometric mean MICs at both 48 and 72 h, showed significant difference between the serotypes A and B of C. neoformans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15218221&dopt=Abstract fluconazole Diflucan