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Comparative evaluation of National Committee for Clinical Laboratory Standards broth macrodilution and agar dilution screening methods for testing fluconazole susceptibility of Cryptococcus neoformans.

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

Department of Medicine, University of Texas Health Science Center at San Antonio, 78284-7881, USA.

A simple screening method for fluconazole susceptibility of Cryptococcus neoformans using 2% dextrose Sabouraud dextrose agar (SabDex) with fluconazole was compared to the National Committee for Clinical Laboratory Standards (NCCLS) broth macrodilution method. By this method, fluconazole-susceptible C. neoformans isolates are significantly smaller on medium with fluconazole than on fluconazole-free medium. Isolates with decreased susceptibility have normal-size colonies on medium containing fluconazole. The 48-h NCCLS broth macrodilution MICs (NCCLS MICs) for isolates with normal-size colonies on 8- or 16-microg/ml fluconazole plates were predicted to be > or =8 or > or =16 microg/ml, respectively. On medium with 16 microg of fluconazole per ml, all strains (84 of 84) for which the NCCLS MICs were <16 microg/ml were correctly predicted, as were all isolates (7 of 7) for which the MICs were > or =16 microg/ml. Agar dilution appears to be an effective screening method for fluconazole resistance in C. neoformans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9574699&dopt=Abstract fluconazole Diflucan



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Antifungal pharmacodynamic characteristics of fluconazole and amphotericin B against Cryptococcus neoformans.

Klepser ME, Wolfe EJ, Pfaller MA.

University of Iowa College of Pharmacy, Iowa City 52242, USA. michael.klepser uiowa.edu

The activity of fluconazole and amphotericin B against three isolates of Cryptococcus neoformans was evaluated, with fluconazole and amphotericin B MICs of 2.0-4.0 mg/L and 1.0 mg/L respectively, using time-kill curve methods. Fluconazole was fungistatic against all isolates tested (<99.9% decrease in cfu from initial inoculum). The fungistatic activity of fluconazole was not enhanced by increasing the concentration of antifungal in solution. In contrast, amphotericin B was markedly fungicidal (> or = 99.9% decrease in cfu from initial inoculum). Both the rate and the extent of amphotericin B activity were enhanced when drug concentration was increased.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9578168&dopt=Abstract fluconazole Diflucan



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Drug pumping mechanisms in Candida albicans.

Cannon RD, Fischer FJ, Niimi K, Niimi M, Arisawa M.

Department of Oral Sciences and Orthodontics, University of Otago, Dunedin, New Zealand.

Multiple drug resistance is becoming a major problem in the treatment of AIDS patients with oropharyngeal candidosis. Candida albicans strains isolated from candidosis patients who do not respond to fluconazole therapy often show azole drug resistance which usually correlates with the expression of C. albicans CDR1, CDR2 or BENr genes, encoding potential drug efflux pumps. The objective of this study was to develop a yeast secretory vesicle transport assay and use this system to study the pumping function of Cdr1 and Benr. The C. albicans CDR1 and BEN r genes were cloned separately into plasmid pVT101-U, to form plasmids pKY1011 and pKN5001 respectively. Plasmids pVT101-U, pKY1011 and pKN5001 were transformed into Saccharomyces cerevisiae SY1, a sec6-4 mutant with a temperature-sensitive mutation in the secretory pathway. SY1 cells transformed with pKY1011 or pKN5001, were more resistant to fluconazole (MICs in both cases 64 microg/ml) than SY1 cells (MIC 32 microg/ml). In addition, cells transformed with pKY1011 were more resistant to cycloheximide (MIC 16 microg/ml) than SY1 cells (MIC 2 microg/ml). Intact secretory vesicles were isolated from SY1 cells expressing Cdr1 and these vesicles accumulated fluconazole in a time dependent manner. These experiments demonstrated that S. cerevisiae secretory vesicles can be used to examine the mechanism of fluconazole transport by putative C. albicans membrane pumps.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9580031&dopt=Abstract fluconazole Diflucan



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Prior fluconazole exposure as an independent risk factor for fluconazole resistant candidosis in HIV positive patients: a case-control study.

Cartledge JD, Midgley J, Gazzard BG.

Department of HIV and GU Medicine, Chelsea and Westminster Health Care Trust, London.

OBJECTIVES: To determine if prior fluconazole exposure was an independent risk factor for fluconazole resistant candidosis in HIV positive patients. METHODS: Twenty five HIV positive cases with fluconazole resistant oral candidosis were matched by CD4 lymphocyte count and time since first episode of candidosis to 25 HIV positive controls with susceptible candidosis. For each individual a history of prior azole prophylaxis was compiled from computerised pharmacy records and review of case notes. RESULTS: The total days of prior azole therapy prescribed was significantly greater for cases than controls. These differences were attributable to prescriptions for secondary prophylaxis against recurrent candidosis, the cases having received significantly longer continuous azole prophylaxis than controls, with no difference in days of prior azole therapy remaining between the two groups if prophylactic prescriptions were excluded. The total cumulative dose of fluconazole received was significantly higher for cases than controls, though mean daily fluconazole doses did not differ significantly between the two groups. CONCLUSION: Even after controlling for degree of immunosuppression and duration of recurrent candidosis, the association between prior azole exposure and fluconazole resistant candidosis remains significant and largely reflects differences in the prescription of secondary antifungal prophylaxis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9582463&dopt=Abstract fluconazole Diflucan



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Pharmacodynamics of fluconazole in a murine model of systemic candidiasis.

Louie A, Drusano GL, Banerjee P, Liu QF, Liu W, Kaw P, Shayegani M, Taber H, Miller MH.

Department of Medicine, Albany Medical College, New York 12208, USA. arnold_louie_at_amc01-3 ccgateway.amc.edu

In this study we defined the pharmacodynamic parameter that optimizes outcome in deep-seated Candida albicans infections treated with fluconazole. Using a murine model of systemic candidiasis, we conducted single-dose dose-ranging studies with fluconazole to determine the dosage of this drug that resulted in a 50% reduction in fungal densities (50% effective dose [ED50]) in kidneys versus the fungal densities in the kidneys of untreated controls. We found that the ED50 of fluconazole given intraperitoneally was 4.56 mg/kg of body weight/day (95% confidence interval, 3.60 to 5.53 mg/kg/day), and the dose-response relationship was best described by an inhibitory sigmoid maximal effect (Emax) curve. To define the pharmacodynamics of fluconazole, we gave dosages lower than, approximating, and higher than the ED50 of fluconazole (range, 3.5 to 5.5 mg/kg/day, equivalent to the ED16 to the ED75) to various groups of infected animals using three dose-fractionation schedules. For each total dose of fluconazole examined, the dose-fractionation schedules optimized the ratio of the area under the concentration-time curve (AUC) to the MIC (the AUC/MIC ratio), the ratio of the maximum concentration of drug in serum (Cmax) to the MIC, and the time that the drug remained above the MIC for the infecting C. albicans isolate. Similar reductions in fungal densities in kidneys were seen between groups that received the same total dose of fluconazole in one, two, or four equally divided doses. Thus, dose-fractionation studies demonstrated that the pharmacodynamic parameter of fluconazole that best predicted outcome was the AUC/MIC ratio.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9593135&dopt=Abstract fluconazole Diflucan



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National surveillance of nosocomial blood stream infection due to Candida albicans: frequency of occurrence and antifungal susceptibility in the SCOPE Program.

Pfaller MA, Jones RN, Messer SA, Edmond MB, Wenzel RP.

Department of Pathology, University of Iowa College of Medicine, Iowa City 52242, USA.

Surveillance of nosocomial blood stream infections (BSI) in the USA between April 1995 and June 1996 revealed that Candida was the fourth leading cause of nosocomial BSI, accounting for 8% of all infections. Fifty-two percent of 379 episodes of candidemia were due to Candida albicans. In vitro susceptibility studies using the 1997 National Committee for Clinical Laboratory Standards reference method demonstrated that 92% of C. albicans isolates were susceptible to 5-fluorocytosine and 90% were susceptible to fluconazole and itraconazole. Geographic variation in susceptibility of fluconazole and itraconazole was observed. Isolates from the Northwest and Southeast regions were more frequently resistant to fluconazole (13.3-15.5%) and to itraconazole (17.2-20.0%) than those from the Northeast and Southwest regions (2.9-5.5% resistant to fluconazole and itraconazole). Continued surveillance for infections caused by C. albicans and other species of Candida among hospitalized patients is recommended.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9597393&dopt=Abstract fluconazole Diflucan



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Role of fluconazole in the management of AIDS-related cryptococcosis, according to daily dosing.

Manfredi R, Chiodo F.

Department of Clinical and Experimental Medicine, University of Bologna, Italy.

No unanimous consent has been reached about treatment guidelines of cryptococcosis in the setting of AIDS, as well as about optimal fluconazole dosing in both initial and suppressive therapy. In order to evaluate the relationship between fluconazole dosing and clinical and microbiological outcome of AIDS-related cryptococcosis, a retrospective study was carried out on 30 consecutive patients. Among the 12 subjects treated with fluconazole doses < 400 mg/day, an unfavorable course was significantly more frequent (early mortality, poor clinical and microbiological response, appearance of early relapses) compared with the 18 patients who received daily doses > or = 400 mg, while no differences were observed between the two treatment groups according to known risk factors for a poor prognosis. When assessing maintenance treatment (22 evaluable cases), the 15 patients receiving oral fluconazole at doses < 200 mg/day showed earlier disease relapse and mortality as opposed to the 7 individuals treated with high-dose fluconazole (> or = 200 mg/day), in the absence of significantly different risk factors for disease recurrence. Our experience pointed out a significant difference in clinical activity of fluconazole in AIDS-related cryptococcosis according to its daily dosing, and suggested 400 and 200 mg as the threshold daily dose for an effective initial and suppressive therapy, respectively, since the probability of treatment failure seemed greater with low-dose drug administration, after controlling data for prognostic markers of disease severity. Controlled studies are warranted, comparing high-dose fluconazole with standard regimens containing amphotericin B in the treatment of AIDS-associated cryptococcosis, and identifying the best fluconazole dosing for both acute-phase and maintenance treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9612611&dopt=Abstract fluconazole Diflucan



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Fluconazole-resistant Candida species in the oral flora of fluconazole-exposed HIV-positive patients.

Hunter KD, Gibson J, Lockhart P, Pithie A, Bagg J.

University of Glasgow, United Kingdom.

The purpose of this study was to examine the effect of preceding fluconazole treatment on the oral mycologic flora and on the sensitivity of oral Candida albicans isolates to fluconazole. Saline oral rinses were collected from 89 HIV-positive patients, of whom 48 had been exposed to fluconazole and 41 were fluconazole-naive. The rinses were cultured on Sabouraud's and Pagano Levin agars, and yeasts were identified by standard methods. Fluconazole sensitivity of C. albicans isolates was measured by disk diffusion assay. C. albicans was isolated from 69% of patients who had received fluconazole and from 93% of the patients who were fluconazole-naive (p < 0.05). Nine other species of yeasts were also isolated, most commonly C. glabrata. Five patients previously exposed to fluconazole harbored fluconazole-resistant C. albicans, whereas no resistance was detected among the patients who were fluconazole-naive (p < 0.01). Sixteen of the patients who were fluconazole-exposed carried yeasts other than C. albicans, compared with only five patients in the fluconazole-naive group (p < 0.01). All of the fluconazole-resistant strains were isolated from patients with low CD4 counts (less than 100 cells/ml) and after lengthy fluconazole exposures. Nevertheless, patients in Charlotte, N.C., who had a greater mean fluconazole exposure time (10.25 +/- 1.41 months) than patients in Glasgow, UK, (0.65 +/- 0.18 months; p < 0.005), did not develop significantly more in vitro resistance or species diversity. This study indicates that long-term fluconazole treatment can have significant effects on the yeast flora of the mouth, particularly in a patient with a CD4 count of less than 100 cells/ml.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9619674&dopt=Abstract fluconazole Diflucan