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Rapid detection of susceptibility to fluconazole in Candida species by a bioluminescence assay of intracellular ATP.

Kretschmar M, Nichterlein T, Kuntz P, Hof H.

Institute of Medical Microbiology and Hygiene, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Germany.

Infections with Candida albicans and Candida species and antifungal resistance are increasingly recognized. The detection of fluconazole resistance is indispensable. We, therefore, compared two rapid methods that use commercially available test kits with the proposed standard of the NCCLS for fluconazole testing. When strains of Candida albicans and Candida species susceptible or resistant to fluconazole were used, measurement of ATP content was superior to the other test because an excellent correlation was obtained already after 5 hours of incubation. The measurement of the metabolic reduction of XTT yielded comparable results, but 24 hours of incubation were necessary.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8902406&dopt=Abstract fluconazole Diflucan



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Effect of fluconazole on viability of Candida albicans over extended periods of time.

Sohnle PG, Hahn BL, Erdmann MD.

Division of Infectious Diseases, Medical College of Wisconsin, Milwaukee 53226, USA.

The treatment of chronic mycoses may expose the infecting organisms to antimicrobial agents for extended periods of time. It is possible that an azole antifungal drug such as fluconazole, with primarily fungistatic activity in standard in vitro susceptibility tests, might be able to damage the fungal cells and reduce their viability over prolonged incubations under nonproliferating conditions. To test this possibility, Candida albicans yeast cells were exposed to various concentrations of fluconazole in RPMI 1640 tissue culture medium for 4 h at 37 degrees C, washed free of the drug, and then incubated at 37 degrees C for a 28-day period; enumeration of the remaining CFU at various times during this period revealed no increased loss of viability for the fluconazole-exposed organisms. However, when fluconazole was added to the organisms maintained in distilled water (with or without pretreatment with the drug), a marked reduction of viability was found. At 14 days of incubation with two strains of C. albicans, negative cultures were found for 7 of 10 and 10 of 11 samples, respectively, containing 1.0 microgram of fluconazole per ml versus 0 of 10 and 1 of 11 control samples (P of < 0.01 and 0.001, respectively). The effect of fluconazole on fungal viability under these conditions became noticeable at approximately 7 days and was greater when the samples were incubated at 37 degrees C rather than 25 degrees C. These findings suggest that fluconazole may have fungicidal effects on fungal cells during prolonged exposures under conditions in which the organisms are prevented from proliferating by lack of nutrients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8913476&dopt=Abstract fluconazole Diflucan



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ZD0870 treatment of murine candidiasis caused by fluconazole resistant isolates of Candida albicans.

Najvar LK, Correa A, James P, Luther MF, Graybill JR.

University of Texas Health Science Center, V.A. Hospital, San Antonio, USA.

Mice were infected intravenously with three fluconazole susceptible and ten fluconazole resistant isolates of Candida albicans then treated with escalating doses of 0.25, 0.5, 1, 2.5, 10 and 40 mg/kg/day of the new antifungal triazole, ZD0870, for 10 days. A minimum protective dose of < 0.25 mg/kg was determined for infections introduced by the three fluconazole susceptible C. albicans and one of the fluconazole resistant isolates whereas doses ranging from 2.5 to 10 mg/kg/day were required for infections induced by seven of the resistant isolates and > or = 40 mg/kg/day for the remainder. Thus, infections caused by fluconazole resistant C. albicans may be successfully treated with ZD0870, though higher doses than those used to treat infections due to susceptible yeast may be required.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8937961&dopt=Abstract fluconazole Diflucan



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Comparative evaluation of three antifungal susceptibility test methods for Candida albicans isolates and correlation with response to fluconazole therapy.

Ruhnke M, Schmidt-Westhausen A, Engelmann E, Trautmann M.

Abteilung Innere Medizin and Poliklinik, Virchow-Klinikum, Humboldt-Universitat, Berlin, Germany. mruhnke .ukrv.de

In vitro susceptibilities were determined for 56 Candida albicans isolates obtained from the oral cavities of 41 patients with human immunodeficiency virus infection. The agents tested included fluconazole, itraconazole, ketoconazole, flucytosine, and amphotericin B. MICs were determined by the broth microdilution technique following National Committee for Clinical Laboratory Standards document M27-P (M27-P micro), a broth microdilution technique using high-resolution medium (HR micro), and the Etest with solidified yeast-nitrogen base agar. The in vitro findings were correlated with in vivo response to fluconazole therapy for oropharyngeal candidiasis. For all C. albicans isolates from patients with oropharyngeal candidiasis not responding to fluconazole MICs were found to be > or = 6.25 micrograms/ml by the M27-P micro method and > or = 25 micrograms/ml by the HR micro method as well as the Etest. However, for several C. albicans isolates from patients who responded to fluconazole therapy MICs found to be above the suggested breakpoints of resistance. The appropriate rank order of best agreement between the M27-P micro method and HR micro method was amphotericin B > fluconazole > flucytosine > ketoconazole > itraconazole. The appropriate rank order with best agreement between the M27-P micro method and the Etest was flucytosine > amphotericin B > fluconazole > ketoconazole > or = itraconazole. It could be concluded that a good correlation between in vitro resistance and clinical failure was found with all methods. However, the test methods used in this study did not necessarily predict clinical response to therapy with fluconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8940474&dopt=Abstract fluconazole Diflucan



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Comparative evaluation of macrodilution and chromogenic agar screening for determining fluconazole susceptibility of Candida albicans.

Patterson TF, Kirkpatrick WR, Revankar SG, McAtee RK, Fothergill AW, McCarthy DI, Rinaldi MG.

Department of Medicine, University of Texas Health Science Center at San Antonio 78284, USA. PATTERSON UTHSCSA.EDU

A simple screening method for fluconazole susceptibility using CHROMagar Candida with fluconazole was compared with the National Committee for Clinical Laboratory Standards (NCCLS) macrobroth method. In this agar dilution method, susceptible Candida albicans colonies are smaller on medium with fluconazole than on fluconazole-free medium. Yeasts with decreased susceptibility have normal-sized colonies on medium containing fluconazole. On agar with 16 micrograms of fluconazole per ml, 32 of 34 strains with NCCLS MICs of > or = 16 micrograms/ml were correctly predicted, as were 66 of 68 with MICs of < 16, an agreement of 96%. On agar with 8 micrograms of fluconazole per ml, 38 of 41 isolates with MICs of > or = 8 were correctly predicted, as were 59 of 61 isolates with MICs of < 8, an agreement of 95%. This agar dilution methods appears to highly correlate with NCCLS macrobroth methods for detection of C. albicans and may be an effective screen for fluconazole susceptibility.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8940483&dopt=Abstract fluconazole Diflucan



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Utility of real-time antifungal susceptibility testing for fluconazole in the treatment of candidemia.

Baddley JW, Patel M, Jones M, Cloud G, Smith AC, Moser SA.

Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, USA. jbaddley uab.edu

Our study prospectively examined the use of real-time antifungal susceptibility testing among 119 patients with candidemia at a large tertiary university medical center over a 1-year period. Susceptibility results to fluconazole were reported to physicians a mean of 5.1 days after the initial positive blood culture for Candida. Physicians believed that receiving antifungal susceptibility testing results was helpful and not infrequently altered therapy on the basis of results. Outcomes, including mortality and resolution of infection, among 20 (17%) patients with fluconazole-resistant and fluconazole-susceptible dose-dependent isolates were relatively poor compared to those among patients with fluconazole-susceptible isolates, but probably reflect severity of illness. Routine susceptibility testing as an adjunct to the treatment of candidemia has significant potential and warrants further study.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15474321&dopt=Abstract fluconazole Diflucan



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T-8581, a new orally and parenterally active triazole antifungal agent: in vitro and in vivo evaluations.

Yotsuji A, Shimizu K, Araki H, Fujimaki K, Nishida N, Hori R, Annen N, Yamamoto S, Hayakawa H, Imaizumi H, Watanbe Y, Narita H.

Research Laboratories, Toyama Chemical Co., Ltd., Japan.

T-8581 is a new water-soluble triazole antifungal agent. The geometric mean IC80s (GM-IC80S; where the IC80 is the lowest drug concentration which reduced the optical density at 630 nm by 80% compared with the optical density at 630 nm of the drug-free control) for Candida albicans were as follows: T-8581, 0.218 microgram/ml; fluconazole; 0.148 microgram/ml; and itraconazole, 0.0170 microgram/ml. For Cryptococcus neoformans the GM-IC80s were as follows: T-8581, 9.28 micrograms/ml; fluconazole, 4.00 micrograms/ml; and itraconazole, 0.119 microgram/ml. For Aspergillus fumigatus the GM-IC80s were as follows: T-8581, 71.0 micrograms/ml; fluconazole, 239 micrograms/ml; and itraconazole, 0.379 microgram/ml. Against systemic candidiasis in mice, the 50% effective doses (ED50s) of T-8581, fluconazole, and itraconazole (given orally) were 0.412, 0.392, and > 320 mg/kg of body weight, respectively. Against systemic aspergillosis in mice, the ED50s of T-8581, fluconazole, and itraconazole (given orally) were 50.5, 138, > 320 mg/kg, respectively. T-8581 was also efficacious when it was given parenterally (ED50, 59.2 mg/kg), while the ED50 of fluconazole given parenterally was > 20 mg/kg. Against systemic aspergillosis in rabbits, T-8581 was more effective than fluconazole and itraconazole in prolonging the life span. The high concentrations of T-8581 were observed in the sera of mice, rats, rabbits and dogs. Species differences in half-lives and areas under the concentration-time curves were observed, with the values for mice, rats, rabbits, and dogs increasing in that order. These results suggest that T-8581 would be a potentially effective antifungal drug for oral and parenteral use.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8980750&dopt=Abstract fluconazole Diflucan



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The in vitro effect of fluconazole on the filamentous form of Pityrosporum ovale.

Faergemann J, Bratel AT.

Department of Dermatology, Sahlgrenska University Hospital, Gothenburg, Sweden.

The antimycotic activity of fluconazole against the filamentous form of Pityrosporum ovale was studied in vitro. P. ovale was grown on human stratum corneum in vitro with and without the addition of different concentrations of fluconazole. In control cultures hyphae were produced in 25% of the cells compared to only 4% after exposure to fluconazole 1 microgram/ml. In control cultures 16% of the fungal cells showed signs of necrosis, due to the normal turnover rate of the cells, compared to 65% of the fungal cells exposed to 1 microgram/ml of fluconazole. In the transmission electron microscope the typical thick-walled fungal cells with their characteristic budding were observed in control cultures. However, after exposure to 1 microgram/ml of fluconazole that P. ovale cells showed extensive signs of necrosis, with loss of internal organelles and disinterruption of the cell wall. The results obtained in this in vitro model mimic the in vivo situation in pityriasis versicolor. There is a parallel between the good results obtained in this system and the good clinical effect of fluconazole in Pityrosporum-related diseases.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8982407&dopt=Abstract fluconazole Diflucan