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Pharmacokinetic interaction of fluconazole and zidovudine in HIV-positive patients.

Brockmeyer NH, Tillmann I, Mertins L, Barthel B, Goos M.

Universitat Essen, Klinik fur Dermatologie, Venerologie und Allergologie, Hufelandstr. 55, Essen D-45147, Germany. dermatology uni-essen.de

To investigate the interaction of fluconazole and zidovudine in HIV-positive non-smoking male patients with AIDS categorized as CDC group IV we studied two groups, each consisting of 10 male, non-smoking, HIV-positive patients with CDC group IV disease, with the patients in the first group additionally suffering from candida esophagitis. In the first group, the pharmacokinetics of 500 mg oral zidovudine were determined both before and after 7 days of treatment with fluconazole 400 mg/d. In the second group, the pharmacokinetics of 200 mg oral fluconazole were determined before and after 14 days of treatment with zidovudine 4 x 250 mg/d. In order to determine the microsomal enzyme activity, the 6-beta-hydroxycortisol/17-hydroxycorticosteroid ratio and antipyrine pharmacokinetic parameters were determined. 6-beta-hydroxycortisol was quantitated by RIA. The 17-hydroxycorticosteroids were determined by a colorimetric method. Zidovudine (ZDV) and zidovudine glucuronide (GZDV), and the fluconazole and antipyrine plasma and urine concentrations were measured by HPLC. Administration of fluconazole resulted in a significant increase in the half-life of zidovudine and antipyrine (0.97 +/- 0.17 h prior to vs. 1.11 +/- 0. 14 h after fluconazole administration and 11.9 +/- 1.9 h prior to vs. 13.7 +/- 3.0 h after fluconazole, respectively) while the 6-beta-hydroxycortisol excretion decreased significantly (472.3 +/- 80.6 microg/24 h before and 340.6 +/- 82.1 microg/24 h after administration of fluconazole). No changes were found in the GZDV plasma kinetics and the ZDV and GZDV urinary excretion. Treatment with ZDV did not have any impact on the half-life of fluconazole. Administration of zidovudine did, however, result in a significant reduction in antipyrine half-life (11.7 +/- 2.0 h before vs. 9.9 +/- 2.3h after ZDV) and a significant increase in 6-beta-hydroxycortisol excretion (438,7 +/- 138.2 microg/24 h before and 684.6 +/- 157.3 microg/24 h after ZDV). Since the antipyrine clearance is altered after administration of ZDV, it is assumed that zidovudine induces cytochrome P450 enzymes. This effect, however, does not alter the pharmacokinetics of fluconazole. High doses of fluconazole can inhibit the plasma elimination of both antipyrine and zidovudine, but the extent of this inhibitory effect is so small that no clinically relevant accumulation is to be expected.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9300934&dopt=Abstract fluconazole Diflucan



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Comparison of the in vitro activities of the echinocandin LY303366, the pneumocandin MK-0991, and fluconazole against Candida species and Cryptococcus neoformans.

Krishnarao TV, Galgiani JN.

Department of Microbiology and Immunology, University of Arizona, Tucson 85724, USA.

Two new glucan synthesis inhibitors, the echinocandin LY303366 and the pneumocandin MK-0991 (formerly L-743,872), were studied for their antifungal activities in vitro in relation to each other and in relation to the activity of the triazole fluconazole. Systematic analysis of broth macrodilution testing by varying the starting inoculum size, medium composition, medium pH, temperature of incubation, length of incubation, or selection of endpoints failed to identify significant differences in antifungal activity for either LY303366 or MK-0991 in comparison to the activity under standard test conditions specified for other antifungal agents in National Committee for Clinical Laboratory Standards (NCCLS) document M27A. Under standardized conditions, both drugs exhibited prominent activity against Candida species including Candida glabrata and Candida krusei but showed little activity against Cryptococcus neoformans. This spectrum of activity differed from that of fluconazole, which exhibited marginal activity against C. glabrata and C. krusei but prominent activity against other Candida species and C. neoformans. For individual strains, broth microdilution MICs of LY303366 and MK-0991 were similar to but frequently higher than broth macrodilution results. In contrast, fluconazole broth microdilution MICs were often lower than broth microdilution results. We conclude that the test conditions specified in NCCLS document M27A are applicable to these two new glucan synthesis inhibitors and that systematic differences between broth microdilution procedures and the broth macrodilution reference standard will need to be addressed before the two test methods can be used interchangeably.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9303393&dopt=Abstract fluconazole Diflucan



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[Biofilm production and antifungal susceptibility patterns of Candida species]

[Article in Turkish]

Yucesoy M, Karaman M.

Dokuz Eylul Universitesi Tip Fakultesi, Mikrobiyoloji ve Klinik Mikrobiyoloji Anabilim Dali, Izmir.

In this study, biofilm production and antifungal susceptibility of various Candida species were examined and compared. A total number of 156 Candida species (94 C. albicans, 21 C. tropicalis, 18 C. glabrata, 12 C. parapsilosis, 9 C. krusei, 1 C. guilliermondii and 1 C. kefyr) isolated from different clinical specimens were included in the study. The biofilm production of the strains was searched by modified tube adherence and microplate methods. Their antifungal susceptibilities against fluconazole and amphotericin B were determined by microdilution method, according to NCCLS M27-A2 standards. Forty three (27.6%) and 26 (16.7%) of the strains were found to be slime producing by tube adherence and microplate methods, respectively. The agreement between the two methods were detected as 65 percent. The rate of biofilm formation by different species ranged between 17% and 55% by tube adherence test and 0 and 48% by microplate method. No significant difference was found between the biofilm production of C. albicans and non-albicans species by tube adherence test (p=0.29). However; a statistically important difference was found when microplate method was considered (p=0.04). MIC50 and MIC90 values for fluconazole ranged between 4-64 microg/ml and 32-->64 microg/ml for different Candida species while these values changed between 0.25-1 microg/ml and 0.5-2 microg/ml for amphotericin B, respectively. Forty-five (28.8%) and 23 (14.7%) of the isolates were found to be dose dependent susceptible and resistant to fluconazole, respectively. Eleven (6.7%) of the strains had MIC values >1 microg/ml for amphotericin B. When the relation between the biofilm production and the susceptibility categories of the strains for amphotericin B were searched, no statistical differences were found by any of the two methods (p=0.12 and p=0.50). A statistically important difference (p=0.03) was determined by tube adherence test and no important difference (p=0.11) was detected by microplate method when fluconazole susceptibility categories were considered. As a conclusion, it has been determined that biofilm production which is a potential virulence factor for Candida species seems to be in agreement with the antifungal susceptibility categories of the strains especially for amphotericin B when the planktonic cells were used for the susceptibility testing.

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Activity of SCH 56592 compared with those of fluconazole and itraconazole against Candida spp.

Law D, Moore CB, Denning DW.

Department of Microbiology, Hope Hospital, Salford, United Kingdom.

The in vitro activity of Schering 56592, a new azole drug, was compared with those of fluconazole and itraconazole against 103 isolates of Candida comprising 10 different species. Schering 56592 was more active than itraconazole and fluconazole, and it was active against many fluconazole-resistant isolates.

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The cost-effectiveness of fluconazole prophylaxis against primary systemic fungal infections in AIDS patients.

Scharfstein JA, Paltiel AD, Freedberg KA.

Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA.

OBJECTIVE: To project the cost-effectiveness of fluconazole for prophylaxis against AIDS-related primary systemic fungal infections. DESIGN: A Markov model with data from the literature. PATIENTS: Hypothetical cohort of 100,000 AIDS patients. INTERVENTION: No prophylaxis, and fluconazole prophylaxis beginning when a patient's CD4 count declined to below 200/mm3, below 100/mm3, or below 50/mm3. RESULTS: The no-prophylaxis policy was associated with a discounted life expectancy of 28.20 months and direct medical costs of $36,100 per person. The < 200/mm3 strategy increased costs to $40,500 and life expectancy to 28.42 months, producing a ratio of $240,000 per year of life saved (YLS). Compared with the no-prophylaxis and < 200/mm3 policies, the intermediate alternatives were less economically efficient. A reduction in fluconazole's cost from $206 to $80 decreased the ratio to $50,000 for the < 200/mm3 strategy. Doubling fungal infection incidence lowered this ratio to $96,000/YLS. CONCLUSIONS: Fluconazole prophylaxis is unlikely to be cost-effective unless its cost is lowered, or it is focused on patients in regions endemic for fungal infections.

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Molecular typing and fluconazole susceptibility of urinary Candida glabrata isolates from hospitalized patients.

Schwab U, Chernomas F, Larcom L, Weems J.

Department of Greenville Hospital System/Clemson University Biomedical Cooperative, South Carolina, USA.

At our community teaching hospital between August 1994 and August 1995, Candida glabrata accounted for 14% of all Candida isolates and for 31% of urinary Candida isolates. The culture site was urine for 68% of C. glabrata isolates compared to 30% of all Candida isolates (p < 0.001, chi 2). To study the association between C. glabrata and isolation from the urine, we analyzed all available C. glabrata urinary isolates over a 3-month period (23 isolates from 20 patients) using electrophoretic karyotyping, random amplified polymorphic DNA analysis, and fluconazole susceptibility testing. Random amplified polymorphic DNA generated eight types, although electrophoretic karyotyping generated 17 types. Combining the two methods resulted in 19 types indicating that urinary C. glabrata strains at our hospital are genetically diverse and the association between C. glabrata and urinary tract isolation does not appear to be due to horizontal transmission of a single or small number of strains. In vitro susceptibility tests showed that C. glabrata isolates from patients receiving fluconazole had significantly higher minimum inhibitory concentrations to fluconazole than those not receiving fluconazole (p < 0.05). Despite a limited number of patients and isolates, our data suggest that selection of less susceptible organisms by the presence of antifungal agents may be an important contributor to increased urinary isolation of C. glabrata from patients in our hospital.

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Point prevalence of oropharyngeal carriage of fluconazole-resistant Candida in human immunodeficiency virus-infected patients.

Martins MD, Lozano-Chiu M, Rex JH.

Department of Internal Medicine, University of Texas Medical School, Houston, USA.

To estimate the prevalence of both clinically evident and asymptomatic carriage of fluconazole-resistant Candida, we prospectively surveyed 128 adults infected with human immunodeficiency virus (HIV). The patients had an average CD4 cell count of 206/mm3. Ninety-seven isolates of Candida were obtained from the oropharynx of 82 patients (64%). Of these 82 patients, 76% carried C. albicans alone; 18%, both albicans and non-albicans isolates; and 6%, non-albicans species alone. Oropharyngeal candidiasis was evident in only 38 (46%) of the 82 patients for whom a culture was positive and was never seen unless C. albicans was present. When MICs were measured by using the National Committee for Clinical Laboratory Standards M27-T methodology and grouped by using recently proposed breakpoints, we found that eight of the 38 patients with oropharyngeal candidiasis and six of the 44 patients who were asymptomatically colonized carried C. albicans isolates resistant to fluconazole (MIC, > or = 64 micrograms/mL); estimated rates of carriage were 21% (95% confidence interval, 10%-37%) and 14% (95% confidence interval, 5%-27%), respectively. Carriage of resistant isolates of C. albicans by HIV-infected adults is more common than previously suspected, and clinicians should be alert to the possible need for either higher doses of fluconazole or alternative treatment modalities.

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The design and validation of a novel intravenous microdialysis probe: application to fluconazole pharmacokinetics in the freely-moving rat model.

Yang H, Wang Q, Elmquist WF.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha 68198-6025, USA.

PURPOSE: The purpose of this study was to design and validate a concentric, flexible intravenous microdialysis probe to determine drug concentrations in blood from the inferior vena cava of a freely-moving animal model. METHODS: An intravenous microdialysis probe was constructed using fused-silica tubing and an acrylonitrile/sodium methallyl sulfonate copolymer hollow fiber. The probe was tested in vitro for the recovery of fluconazole and UK-54,373, a fluconazole analog used for probe calibration by retrodialysis. Subsequent in vivo validation was done in rats (n = 7) that had a microdialysis probe inserted into the inferior vena cava via the femoral vein, and the femoral artery was cannulated for simultaneous blood sampling. Comparisons of fluconazole pharmacokinetic parameters resulting from the two sampling methods were performed at 2 and 10 days after probe implantation. RESULTS: There were no statistical differences between the microdialysis sampling and conventional blood sampling methods for the T1/2, Cl, Vdss, and dose-normalized AUC by paired t-test (p > 0.05) for repeated dosing at day 2 and day 10 after probe placement. The probe recovery, as determined by retrodialysis, significantly decreased over the ten day period. This finding indicates the necessity for frequent recovery determinations during a long-term blood microdialysis experiment. CONCLUSIONS: These results show that microdialysis sampling in the inferior vena cava using this unique and robust probe design provides an accurate method of determining blood pharmacokinetics in the freely-moving rat for extended experimental periods. The probe design allows for a simple surgical placement into the inferior vena cava which results in a more stable animal preparation for long-term sampling and repeated-measures experimental designs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9358561&dopt=Abstract fluconazole Diflucan