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Fluconazole binding and sterol demethylation in three CYP51 isoforms indicate differences in active site topology.

Bellamine A, Lepesheva GI, Waterman MR.

Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA. aouatef.bellamine vanderbilt.edu

14alpha-Demethylase (CYP51) is a key enzyme in all sterol biosynthetic pathways (animals, fungi, plants, protists, and some bacteria), catalyzing the removal of the C-14 methyl group following cyclization of squalene. Based on mutations found in CYP51 genes from Candida albicans azole-resistant isolates obtained after fluconazole treatment of fungal infections, and using site-directed mutagenesis, we have found that fluconazole binding and substrate metabolism vary among three different CYP51 isoforms: human, fungal, and mycobacterial. In C. albicans, the Y132H mutant from isolates shows no effect on fluconazole binding, whereas the F145L mutant results in a 5-fold increase in its IC(50) for fluconazole, suggesting that F145 (conserved only in fungal 14alpha-demethylases) interacts with this azole. In C. albicans, F145L accounts, in part, for the difference in fluconazole sensitivity reported between mammals and fungi, providing a basis for treatment of fungal infections. The C. albicans Y132H and human Y145H CYP51 mutants show essentially no effect on substrate metabolism, but the Mycobacterium tuberculosis F89H CYP51 mutant loses both its substrate binding and metabolism. Because these three residues align in the three isoforms, the results indicate that their active sites contain important structural differences, and further emphasize that fluconazole and substrate binding are uncoupled properties.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15314102&dopt=Abstract fluconazole Diflucan



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A synergistic effect of Carica papaya latex sap and fluconazole on Candida albicans growth.

Giordani R, Gachon C, Moulin-Traffort J, Regli P.

Laboratoire de Botanique, Cryptogamie et Biologie Cellulaire, Universite de la Mediterranee, Faculte de Pharmacie, Marseille, France.

A mixture of Carica papaya latex (0.41 mg protein ml-1) and fluconazole (2 micrograms ml-1) showed a synergistic action on the inhibition of Candida albicans growth. Thus, with this mixture an equivalent inhibition rate was observed to that obtained when C. albicans was cultured in a medium supplemented with a two-fold concentration (4 micrograms ml-1) of fluconazole alone. This synergistic effect resulted in partial cell wall degradation as indicated by transmission electron microscopy observations. An increase of fluconazole concentration from 2 micrograms ml-1 to 4 micrograms ml-1 involved a small decrease of MIC 80% from latex (150 to 130 micrograms protein ml-1). Measure of MIC 80% from fluconazole mixed with latex in a subinhibitory concentration (85 micrograms protein ml-1) allows the determination of an effective fluconazole concentration (4 micrograms ml-1) inferior to mean plasmatic dose observed in human therapy. The potential therapeutic use of latex in combination with a synthetic antifungal is discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9470408&dopt=Abstract fluconazole Diflucan



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Fluconazole susceptibility of Candida isolates from oropharyngeal candidosis.

Dannaoui E, Lacoste V, Prat C, Piens MA.

Laboratoire de Parasitologie et Mycologie Medicale, Faculte de Medecine Rockefeller, Lyon, France.

Fifty strains of Candida isolated from 38 patients with oropharyngeal candidosis were tested in vitro for fluconazole susceptibility with a disk diffusion test and for determination of minimal inhibitory concentrations (MICs). For 25 patients treated with fluconazole, the relationship between in vitro susceptibility and clinical outcome was analysed. A good correlation between in vitro results and therapeutic efficacy was found. In only one case was treatment failure associated with a susceptible strain. Mixed cultures of Candida albicans and non-albicans Candida species were not uncommon and, more interestingly, some samples contained different strains of C. albicans with varied fluconazole susceptibilities. Good agreement was observed between the two techniques used for fluconazole susceptibility testing.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9476510&dopt=Abstract fluconazole Diflucan



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[Current treatment of candidemia in non-neutropenic patients. Amphotericin B or fluconazole? A retrospective study of 62 consecutive patients]

[Article in Spanish]

Cobo Reinoso P, Aguado Garcia JM, Lumbreras Bermejo C, Perez Vela JL, Caballero Cubedo R, Sanz Sanz F, Noriega Rodriguez AR.

Unidad de Enfermedades Infecciosas, Hospital 12 de Octubre, Madrid.

BACKGROUND: To analyze the epidemiologic characteristics of non-neutropenic patients with candidemia in a general hospital and the advantages and disadvantages of treatment with amphotericin B or fluconazole. PATIENTS AND METHODS: A total of 62 adult non-neutropenic patients with candidemia and treated with amphotericin B (n = 35) or fluconazole (n = 27) were studied. All episodes were considered to be associated with infection in a vein catheter. The demographic characteristics, risk factors for the development of candidemia, Candida species recovered from blood culture, underlying diseases, and clinical manifestations in both groups were compared. The evolution regarding secondary effects developed with both drugs, therapy failures, long term complications, and overall mortality rate associated with candidemia were analyzed. RESULTS: Both groups were comparable with the exception of the percentage of patients infected with species different from Candida albicans, which was higher in the group of patients who received amphotericin B (57%) than in the fluconazole group (26%) (p = 0.02), and in that patients with severe renal failure or AIDS had received preferentially fluconazole. There were no statistically significant differences regarding the evolution of patients treated with amphotericin B or fluconazole with the following factors: therapy failure (27% versus 19%; p = 0.7), overall mortality rate (40% versus 44%; p = 0.6), and mortality directly related to candidemia (33% versus 30%). Mortality was significantly higher among patients who had not their vein catheters removed early (78%) compared with those who had their vein catheters removed early (34%) (p = 0.01). Sixty-six percent of patients treated with amphotericin developed some severe secondary effect, whereas no patient in the fluconazole group developed such effects. CONCLUSIONS: Both amphotericin B and fluconazole seem to be effective drugs for the treatment of vein catheter related candidemia in the non-neutropenic patient, although fluconazole is far less toxic. The early removal of the vein catheter plays a prognostic role with at least the same relevance than the type of antifungal therapy chosen.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9477669&dopt=Abstract fluconazole Diflucan



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Evaluation of the susceptibility of pathogenic Candida species to fluconazole. Fluconazole Global Susceptibility Study Group.

Bille J, Glauser MP.

Institute of Microbiology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

A fluconazole 25 microg disk diffusion test was used to test 2230 consecutively isolated Candida strains from 42 different hospital laboratories in 23 countries. Ninety seven percent of 1634 Candida albicans isolates and 83.4% of 596 non-Candida albicans isolates were susceptible to fluconazole, applying the proposed breakpoints (> or = 26 mm for susceptible strains and 18-25 mm for dose-dependent susceptible strains). This is the first hospital laboratory study to evaluate a large number and wide range of sequential Candida isolates from patients with all types of hospital infections. The fluconazole disk diffusion test appears to be a low-cost, reproducible, and accurate means of assessing the in vitro susceptibility of Candida isolates.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9495675&dopt=Abstract fluconazole Diflucan



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Effect of repeated dosing on the pharmacokinetics of oral fluconazole in bone marrow transplant patients.

el-Yazigi A, Ellis M, Ernst P, Hussein R, Baillie FJ.

Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

We examined the pharmacokinetics of fluconazole in 11 bone marrow transplant patients after multiple oral daily dose of 200 mg of this drug. Blood was sampled at different intervals on day 1, day 13, and day 27. No dose was given on day 2, day 14, and day 28 to allow the concentration-time data to be collected over 48 hours. The 24 hour urine was also collected, and fluconazole was analyzed in both plasma and urine by a high performance liquid chromatography. The plasma concentration-time data were best described by the one-compartment model with first-order absorption. The overall inter-day change and the difference between day 1 and day 27 in the rate constant for absorption (ka), peak plasma concentration (Cmax), through plasma concentration (Cmin), time-to-peak (tmax), area-under-the-curve 0-24 (AUC0-24), rate constant for elimination (ka), mean residence time after oral administration (MRTor), and fraction of the dose excreted unchanged in urine 24 hours (fu24) were significant (P < or = 0.0029 and P < or = 0.01, respectively). However, the difference between day 1 and day 13 was significant (P < or = 0.05) only in ka, tmax, Cmax, Cmin, and AUC0-24, and between day 13 and day 27 was significant (P < or = 0.05) only in ka, Cmin, ka, and MRTor. There was no significant inter-day change in the renal clearance. The significant (P < or = 0.05) increases in Cmax, Cmin, and AUC0-24 after the dose given on day 13 as compared with day 1, and in Cmin on day 27 as compared with day 13 indicate that, in contrast to volunteers, the steady state condition was not reached on day 13 and possibly not on day 27 in these patients. This perhaps should be taken into account when prescribing fluconazole to seriously ill patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9505996&dopt=Abstract fluconazole Diflucan



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Amphotericin B colloidal dispersion combined with flucytosine with or without fluconazole for treatment of murine cryptococcal meningitis.

Diamond DM, Bauer M, Daniel BE, Leal MA, Johnson D, Williams BK, Thomas AM, Ding JC, Najvar L, Graybill JR, Larsen RA.

Department of Medicine (Infectious Diseases), University of Southern California, Los Angeles 90033, USA.

Studies with animals and in vitro studies have demonstrated that flucytosine plus amphotericin B or fluconazole has significantly improved mycologic activity against meningitis caused by Cryptococcus neoformans compared to the activity of amphotericin B or fluconazole used alone. However, few doses have been tested in combination. This study evaluated the antifungal efficacy of amphotericin B colloidal dispersion (ABCD) combined with flucytosine with and without fluconazole in a murine model of cryptococcal meningitis. The following dosages were tested: ABCD at 0 to 12.5 mg/kg of body weight given intravenously 3 days/week, flucytosine at 0 to 110 mg/kg/day, and fluconazole at 0 to 50 mg/kg/day. Meningitis was established in male BALB/c mice by intracerebral injection of C. neoformans. Treatment with flucytosine with or without fluconazole dissolved in the sole source of drinking water was started on day 2; animals were sacrificed at 16 days, and the numbers of fungal colonies in the brain were quantified. A survival rate of 100% was achieved with ABCD plus flucytosine without fluconazole; however, the addition of fluconazole was required to prevent weight loss (P < 0.00001) and to achieve the maximum antifungal effect (P < 0.00001). The only region of dose combinations for which the 99% confidence intervals were less than 100 CFU/g of brain was defined by ABCD at 5.0 to 7.5 mg/kg combined with flucytosine at 20 to 60 mg/kg/day and fluconazole at 30 to 40 mg/kg/day. The triple combination of ABCD plus flucytosine and fluconazole was necessary to achieve the greatest antifungal activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9517927&dopt=Abstract fluconazole Diflucan



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In vitro activity of a new oral triazole, BMS-207147 (ER-30346)

Fung-Tomc JC, Huczko E, Minassian B, Bonner DP.

Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA. joanvc.vfung-tomc ccmail.bms.com

The antifungal activity of BMS-207147 (also known as ER-30346) was compared to those of itraconazole and fluconazole against 250 strains of fungi representing 44 fungal species. MICs were determined by using the National Committee for Clinical Laboratory Standards (NCCLS)-recommended broth macrodilution method for yeasts, which was modified for filamentous fungi. BMS-207147 was about two- to fourfold more potent than itraconazole and about 40-fold more active than fluconazole against yeasts. With the NCCLS-recommended resistant MIC breakpoints of > or = 1 microg/ml for itraconazole and of > or = 64 microg/ml for fluconazole against Candida spp., itraconazole and fluconazole were inactive against strains of Candida krusei and Candida tropicalis. In contrast, all but 9 (all C. tropicalis) of the 116 Candida strains tested had BMS-207147 MICs of < 1 microg/ml. The three triazoles were active against about half of the Candida glabrata strains and against all of the Cryptococcus neoformans strains tested. The three triazoles were fungistatic to most yeast species, except for BMS-207147 and itraconazole, which were fungicidal to cryptococci. BMS-207147 and itraconazole were inhibitory to most aspergilli, and against half of the isolates, the activity was cidal. BMS-207147 and itraconazole were active, though not cidal, against most hyaline Hyphomycetes (with the exception of Fusarium spp. and Pseudallescheria boydii), dermatophytes, and the dematiaceous fungi and inactive against Sporothrix schenckii and zygomycetes. Fluconazole, on the other hand, was inactive against most filamentous fungi with the exception of dermatophytes other than Microsporum gypseum. Thus, the spectrum and potency of BMS-207147 indicate that it should be a candidate for clinical development.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9527778&dopt=Abstract fluconazole Diflucan