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Intraocular use of fluconazole in the management of ocular fungal infection.

Su CY, Lin CP, Wang HZ, Su MY, Tsai RK, Wu KY, Sheu MM.

Department of Ophthalmology, Kaohsiung Medical College, Taiwan, Republic of China.

In this study, we investigate the efficacy and safety of intraocular use of fluconazole in the treatment of ocular fungal infection. Ten patients with intraocular fungal infections were examined. Among these patients, eight were infected with keratomycosis with intraocular spreading, one had postoperative fungal endophthalmitis after cataract operation with an intraocular lens implant, and another suffered from endogenous fungal endophthalmitis. In addition to the conventional local application with or without systemic administration of antifungal drugs, all ten patients were treated with intraocular administration of 5-10 micrograms/ml of fluconazole. The ocular fungal infections resolved in nine patients without obvious side effect. One failed in the antifungal treatment with loss of vision. In our experience, the results revealed that fluconazole is a safe and effective antifungal agent that can be administered intraocularly. We suggest that intraocular administration of this drug could be considered as an alternative or additional choice for the treatment of severe ocular fungal infections.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10330801&dopt=Abstract fluconazole Diflucan



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[In vitro activity of fluconazole against Candida albicans isolated from blood culture]

[Article in Spanish]

Peman J, Canton E, Orero A, Ubeda P, Viudes A, Pastor A, Gobernado M.

Servicio de Microbiologia, Hospital Universitario La Fe, Valencia.

The in vitro activity of fluconazole against 65 Candida albicans isolated from blood culture in 1995, 1996 and 1997 was studied by macrodilution and disk diffusion methods. The MIC ranged from 0.03 to 64 microg/ml, with 93.6% of strains being inhibited with 1 microg/ml fluconazole; the mode MIC was 0.25 microg/ml. Using this method, only one strain was resistant and another was susceptible depending on the dose. By diffusion, eight strains were susceptible, 53 intermediate, and four resistant. The strains susceptible by dilution were also susceptible by diffusion, but the strains resistant by diffusion were not always resistant by dilution. We find it therefore useful to determine the MIC of fluconazole to the C. albicans resistant by diffusion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10336314&dopt=Abstract fluconazole Diflucan



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Genome-wide expression profiling reveals genes associated with amphotericin B and fluconazole resistance in experimentally induced antifungal resistant isolates of Candida albicans.

Barker KS, Crisp S, Wiederhold N, Lewis RE, Bareither B, Eckstein J, Barbuch R, Bard M, Rogers PD.

Department of Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, Memphis, USA.

OBJECTIVES: The aim of this study was to identify changes in the gene expression profile of Candida albicans associated with the acquisition of experimentally induced resistance to amphotericin B and fluconazole. METHODS: C. albicans SC5314 was passed in increasing concentrations of amphotericin B to generate isolate SC5314-AR. Susceptibility testing by Etest revealed SC5314-AR to be highly resistant to both amphotericin B and fluconazole. The gene expression profile of SC5314-AR was compared with that of SC5314 using DNA microarray analysis. Sterol composition was determined for both strains. RESULTS: Upon examination of MICs of antifungal compounds, it was found that SC5314-AR was resistant to both amphotericin B and fluconazole. By microarray analysis a total of 134 genes were found to be differentially expressed, that is up-regulated or down-regulated by at least 50%, in SC5314-AR. In addition to the cell stress genes DDR48 and RTA2, the ergosterol biosynthesis genes ERG5, ERG6 and ERG25 were up-regulated. Several histone genes, protein synthesis genes and energy generation genes were down-regulated. Sterol analysis revealed the prevalence of sterol intermediates eburicol and lanosterol in SC5314-AR, whereas ergosterol was the predominant sterol in SC5314. CONCLUSION: Along with changes in expression of these ergosterol biosynthesis genes was the accumulation of sterol intermediates in the resistant strain, which would account for the decreased affinity of amphotericin B for membrane sterols and a decreased requirement for lanosterol demethylase activity in membrane sterol production. Furthermore, other genes are implicated as having a potential role in the polyene and azole antifungal resistant phenotype.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15201233&dopt=Abstract fluconazole Diflucan



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Interaction between fluconazole and midazolam in intensive care patients.

Ahonen J, Olkkola KT, Takala A, Neuvonen PJ.

Department of Anaesthesia, University of Helsinki, Finland.

BACKGROUND: Midazolam is used for sedation of intensive care unit (ICU) patients and it is extensively metabolised by CYP3A4 enzymes. The antimycotic fluconazole is often used in these patients as well and has been shown to inhibit CYP3A4-mediated drug metabolism. METHODS: In a study of the effect of fluconazole on midazolam in the ICU, ten mechanically ventilated patients (age 29 to 61 years, 8 male) sedated with a stable midazolam infusion were enrolled after a decision to start fluconazole treatment. Fluconazole was infused for 30 min at intervals of 24 h, with an initial dose of 400 mg and following doses of 200 mg. The midazolam infusion rate remained unchanged during the study period of 48 h. Plasma concentrations of midazolam, alpha-hydroxymidazolam, and alpha-hydroxymidazolam conjugate were determined at baseline, and at 6, 12, 18, 24, 36, and at 48 h thereafter. RESULTS: Concentrations of midazolam were significantly increased (range 0 to 4-fold, P < 0.05) after start of fluconazole treatment. These increases were most marked in patients with renal failure. During the study period, the ratio of alpha-hydroxymidazolam to midazolam decreased progressively (P < 0.05). CONCLUSION: In ICU patients receiving fluconazole, reduction of midazolam infusion rate should be considered if the degree of sedation is found to be increasing.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10341997&dopt=Abstract fluconazole Diflucan



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In vitro susceptibilities of Candida and Cryptococcus neoformans isolates from blood cultures of neutropenic patients.

Hoban DJ, Zhanel GG, Karlowsky JA.

Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada. dhoban hsc.mb.ca

Fluconazole-resistant Candida albicans and intrinsically fluconazole-resistant Candida species have been reported as bloodstream isolates. However, an association between the isolation of fluconazole-resistant Candida from the bloodstream and patient risk factors for fungemia has not been established. The purpose of this study was to determine the prevalence of fluconazole resistance in bloodstream isolates of Candida species and Cryptococcus neoformans collected from patients with neutropenia, one of the most important risk factors for fungemia. MICs of voriconazole, fluconazole, itraconazole, ketoconazole, amphotericin B, and flucytosine were determined by the National Committee for Clinical Laboratory Standards M27-A method (1997). Voriconazole, on a per-weight basis, was the most active azole tested. Fluconazole resistance (MIC >/= 64 microg/ml) was not identified in any of the C. albicans (n = 513), Candida parapsilosis (n = 78), Candida tropicalis (n = 62), or C. neoformans (n = 38) isolates tested.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10348771&dopt=Abstract fluconazole Diflucan



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A comparative evaluation of Etest and broth microdilution methods for fluconazole and itraconazole susceptibility testing of Candida spp.

Martin-Mazuelos E, Gutierrez MJ, Aller AI, Bernal S, Martinez MA, Montero O, Quindos G.

Servicio de Microbiologia Clinica, Hospital Universitario de Valme, Sevilla, Spain.

The Etest strip is a promising tool of broad application in clinical microbiology. The method provides MIC readings and is easier to perform than broth microdilution. We carried out a study to compare the MICs of fluconazole and itraconazole obtained by the Etest with those obtained by broth microdilution, performed according to the guidelines of the NCCLS document M27-A, with 402 clinical isolates (360 Candida albicans, 17 Candida tropicalis, nine Candida krusei, nine Candida glabrata and seven Candida parapsilosis) and seven control isolates. The agreement between MICs by the two methods (at +/- 2 dilutions) was 74.5% for fluconazole and 61.4% for itraconazole. These results suggest that further development is necessary to standardize the medium and incubation conditions before introduction of the Etest as a routine method in the clinical microbiology laboratory for fluconazole and itraconazole susceptibility testing.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10350375&dopt=Abstract fluconazole Diflucan



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Increased adherence of fluconazole-resistant isolates of Candida species to explanted esophageal mucosa.

Lyman CA, Garrett KF, Peter J, Gonzalez C, Walsh TJ.

Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892, USA. lymanc mail.nih.gov

The adherence of fluconazole-resistant and fluconazole-susceptible isolates of Candida albicans to explanted rabbit esophageal mucosa was examined in vivo. Among six Candida albicans isolates collected from HIV-infected patients, three fluconazole-resistant (MIC > 64 microg/ml) isolates attached more avidly than three fluconazole-susceptible strains (MIC < or = 0.5 microg/ml) to esophageal mucosa (P < or = 0.05). When three strains each of six different Candida spp. were compared, the more inherently fluconazole-resistant isolates adhered more avidly in the following order: Candida glabrata>Candida krusei>Candida albicans fluconazole-sensitive>Candida tropicalis>Candida parapsilosis. Nonetheless, fluconazole-resistant Candida albicans demonstrated the greatest degree of adherence in comparison to all fluconazole-susceptible Candida albicans (P<0.001) and to all Candida spp. tested (P<0.001). Thus, the refractoriness of esophageal candidiasis in patients infected with fluconazole-resistant isolates may be related to both in vitro drug resistance and increased mucosal adherence.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10357058&dopt=Abstract fluconazole Diflucan



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Fluconazole susceptibilities of bloodstream Candida sp. isolates as determined by National Committee for Clinical Laboratory Standards method M27-A and two other methods.

Canton E, Peman J, Carrillo-Munoz A, Orero A, Ubeda P, Viudes A, Gobernado M.

Unidad de Bacteriologia Experimental-Centro de Investigacion, Hospital Universitario La Fe, 46009 Valencia, Spain. ecanton san.gva.es

The in vitro activity of fluconazole against 143 Candida spp. obtained from the bloodstreams of 143 hospitalized patients from 1995 to 1997 was studied. Susceptibility tests were carried out by two macrodilution methods, the M27-A and a modified M27-A method (0. 165 M, pH 7/morpholinepropanesulfonic acid-buffered RPMI 1640 medium supplemented with 20 g of D-dextrose per liter), and by the agar diffusion method (with 15-microg fluconazole [Neo-Sensitab] tablets). With 2 microg of fluconazole per ml, 96.92% of 65 C. albicans isolates, 86.2% of 58 C. parapsilosis isolates 7 of 8 C. tropicalis isolates, and 1 of 6 C. glabrata isolates were inhibited. Only one strain of C. albicans and one strain of C. tropicalis were resistant. The agreement between the two macrodilution methods was greater than 90% within +/-2 log2 dilutions for all strains except C. glabrata (83.3%) and C. tropicalis (87.5%). Generally, MICs were 1 log2 dilution lower in glucose-supplemented RPMI 1640 medium. No correlation between zone sizes and MICs was found. All strains susceptible by the diffusion test were susceptible by the dilution method, but the converse was not necessarily true. Interestingly, inhibition zones were smaller for C. albicans, for which the geometric mean MIC was 0.29 microg/ml and the mean inhibition zone diameter was 25.7 mm, while for C. parapsilosis the geometric mean MIC was 0.96 microg/ml and the mean inhibition zone diameter was 31. 52 mm. In conclusion, the two macrodilution methods give similar results. The modified M27-A method with 2% dextrose has the advantage of shortening the incubation time and simplifying the endpoint determination.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10364585&dopt=Abstract fluconazole Diflucan