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The effect of empiric and prophylactic treatment with fluconazole on yeast isolates in a surgical trauma intensive care unit.

Safran DB, Dawson E.

Surgical Trauma Intensive Care Unit, University of South Alabama Medical Center, Mobile, USA.

OBJECTIVE: To assess the effect of aggressive antifungal prophylaxis and empiric antifungal therapy using fluconazole on the mycotic microbiology and associated infectious complications in a surgical intensive care unit. DESIGN: Retrospective review of a cohort of critically ill surgical patients treated during an 11-month period. SETTING: Surgical intensive care unit, university hospital, state-designated level I trauma center. PATIENTS: All patients treated with fluconazole during the study. MAIN OUTCOME MEASURES: Positive fungal cultures obtained after commencement of antifungal prophylaxis or antifungal treatment with fluconazole. Overall and infectious mortality rates for patients with positive cultures were also measured. RESULTS: Of 72 surgical patients who were treated with fluconazole; 16 (22%) had secondary mycoses. Fourteen (88%) of these patients were receiving fluconazole as antifungal prophylaxis or as empiric treatment of suspected but unproved infection. The predominant organisms isolated from these 16 patients were Candida glabrata (41%) and Candida parapsilosis (41%). Overall mortality for this group was 44%, and infectious mortality was 38%. The infectious mortality rate was significantly higher than the rate found in patients who were successfully treated with fluconazole for primary mycoses, and who did not have secondary infections with resistant organisms (mortality, 9%; P < .01, chi 2). CONCLUSIONS: Emergence of resistant species after treatment with fluconazole does occur in surgical patients, and suggests that the development of a secondary fungal infection with a resistant organism may be associated with a poor prognosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9366710&dopt=Abstract fluconazole Diflucan



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In vitro antifungal activity of novel azole derivatives with a morpholine ring, UR-9746 and UR-9751, and comparison with fluconazole.

Stevens DA, Aristizabal BH.

Department of Medicine, Santa Clara Valley Medical Center, San Jose, CA 95128-2699, USA.

Thirty-three patient fungal isolates were studied by broth macrodilution methods for susceptibility to novel azole derivatives with a morpholine ring, UR-9746 and UR-9751, and fluconazole. MICs (micrograms/ml) ranged widely, but none had lower MICs for Candida albicans or Cryptococcus neoformans than UR-9751. Fluconazole and UR-9751 had the most activity versus other Candida species. Activity was demonstrated versus endemic fungal pathogens. Aspergillus species were generally resistant, although modest activity was seen. UR-9746 and UR-9751 are active in vitro, with a potency comparable to that of fluconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9368086&dopt=Abstract fluconazole Diflucan



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A new triazole, voriconazole (UK-109,496), blocks sterol biosynthesis in Candida albicans and Candida krusei.

Sanati H, Belanger P, Fratti R, Ghannoum M.

Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, California 90509, USA.

Voriconazole (UK-109,496) is a novel triazole derivative with potent broad-spectrum activity against various fungi, including some that are inherently resistant to fluconazole, such as Candida krusei. In this study we compared the effect of subinhibitory concentrations of voriconazole and fluconazole on sterol biosynthesis of fluconazole-resistant and -susceptible Candida albicans strains, as well as C. krusei, in an effort to delineate the precise mode of action of voriconazole. Voriconazole MICs ranged from 0.003 to 4 microg/ml, while fluconazole MICs ranged from 0.25 to >64 microg/ml. To investigate the effects of voriconazole and fluconazole on candidal sterols, yeast cells were grown in the absence and presence of antifungals. In untreated C. albicans controls, ergosterol was the major sterol (accounting for 53.6% +/- 2.2% to 71.7% +/- 7.8% of the total) in C. albicans and C. krusei strains. There was no significant difference between the sterol compositions of the fluconazole-susceptible and -resistant C. albicans isolates. Voriconazole treatment led to a decrease in the total sterol content of both C. albicans strains tested. In contrast, exposure to fluconazole did not result in a significant reduction in the total sterol content of the three candidal strains tested (P > 0.5). Gas-liquid chromatographic analysis revealed profound changes in the sterol profiles of both C. albicans strains and of C. krusei in response to voriconazole. This antifungal agent exerted a similar effect on the sterol compositions of both fluconazole-susceptible and -resistant C. albicans strains. Interestingly, a complete inhibition of ergosterol synthesis and accumulation of its biosynthetic precursors were observed in both strains treated with voriconazole. In contrast, fluconazole partially inhibited ergosterol synthesis. Analysis of sterols obtained from a fluconazole-resistant C. albicans strain grown in the presence of different concentrations of voriconazole showed that this agent inhibits ergosterol synthesis in a dose-dependent manner. In C. krusei, voriconazole significantly inhibited ergosterol synthesis (over 75% inhibition). C. krusei cells treated with voriconazole accumulated the following biosynthetic intermediates: squalene, 4,14-dimethylzymosterol, and 24-methylenedihydrolanosterol. Accumulation of these methylated sterols is consistent with the premise that this agent functions by inhibiting fungal P-450-dependent 14alpha-demethylase. As expected, treating C. krusei with fluconazole minimally inhibited ergosterol synthesis. Importantly, our data indicate that voriconazole is more effective than fluconazole in blocking candidal sterol biosynthesis, consistent with the different antifungal potencies of these compounds.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9371355&dopt=Abstract fluconazole Diflucan



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Effectiveness of quinolone antibiotics in modulating the effects of antifungal drugs.

Sugar AM, Liu XP, Chen RJ.

Evans Memorial Department of Clinical Research, Boston Medical Center, Massachusetts 02181, USA. asugar med-med1.bu.edu

Quinolone antibacterial drugs inhibit DNA gyrase, a type 2 topoisomerase. Since topoisomerases are present in eukaryotic cells, it was of interest to evaluate the antifungal activities of two clinically available quinolones, ciprofloxacin and trovafloxacin, alone and in combination with amphotericin B or fluconazole, in vitro against Candida albicans and in a murine model of invasive candidiasis. The in vitro activity of trovafloxacin was also tested against other yeasts and molds. In vitro, trovafloxacin exhibited no antifungal activity against any of the fungi (MIC, >250 microg/ml). There was also no effect of the quinolone on the in vitro activity of either antifungal drug. Marked antifungal effects were seen, however, in the murine model of candidiasis. In all experiments, control mice infected intravenously with C. albicans were dead by day 24. While either quinolone had minimal effects on survival of mice when used alone in oral doses of up to 40 mg/kg twice daily, the combination of the quinolone with fluconazole (40 or 80 mg/kg given twice daily by oral gavage) was more effective in prolonging survival than was fluconazole alone. Colony counts of kidneys on days 12 and 30 showed similar reductions in C. albicans recovered from mice treated with fluconazole with or without trovafloxacin or amphotericin B with or without trovafloxacin. Survival of mice treated with a suboptimal dose of amphotericin B (0.2 mg/kg/day) was also improved when trovafloxacin (40 mg/kg) given twice daily was included (0 versus 27%, respectively; P < 0.05). While the mechanisms of action of the combination of trovafloxacin and amphotericin B or fluconazole are unclear, further work focused on fungal topoisomerase inhibition and the mechanism of the antifungal effect of quinolone antibacterial drugs is warranted.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9371359&dopt=Abstract fluconazole Diflucan



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Unresponsive HIV-related oro-oesophageal candidosis--an evaluation of two new in-vitro azole susceptibility tests.

Cartledge JD, Midgley J, Petrou M, Shanson D, Gazzard BG.

HIV/GU Medicine Unit, Chelsea & Westminster Hospital, London, UK.

Azole-resistant HIV-related candidosis is increasingly recognized. We evaluated two new in-vitro susceptibility tests (the NCCLS proposed MIC method and Odds' assessment of relative growth in single anti-fungal concentration) as predictors of the clinical outcome of 66 HIV-positive patients with oral candidosis, of whom 22 were azole naive, 27 had always previously responded to azole therapy and 17 had persistent candidosis unresponsive to 7 days of standard azole therapy. None of the last group responded to increased daily doses of fluconazole or itraconazole capsules, though nine responded to itraconazole cyclodextrin solution 200 mg bd for 7 days. Our findings suggest that agreement between the Odds' test and the MIC method was excellent (96-98%) and that both could discriminate between isolates of azole-unresponsive patients and those of azole-responsive patients. For fluconazole susceptibility an MIC > or = 8 mg/L detected fluconazole-unresponsive patients with a sensitivity of 94% and specificity of 100%; Odds' method achieved 100% sensitivity and 100% specificity using all cut-offs between 77 and 88% relative growth in medium containing fluconazole (10(-5) M; 3 mg/L). For itraconazole and ketoconazole agreement between MIC and Odds' method was again excellent (98% and 96%, respectively) but five azole-unresponsive patients appeared to have ketoconazole-susceptible organisms as defined by both tests, and similarly 11 appeared to have itraconazole-susceptible organisms by both tests despite failing to respond to the capsule formulation of the drug. Of these 11, eight responded to itraconazole solution; this finding implies that itraconazole capsule failure might represent poor drug absorption rather than fungal resistance.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9372421&dopt=Abstract fluconazole Diflucan



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Pharmacokinetics of fluconazole in children requiring peritoneal dialysis.

Wong SF, Leung MP, Chan MY.

Department of Paediatrics, Grantham Hospital, Aberdeen, Hong Kong.

After major open heart surgery, a significant number of infants and children are dependent on peritoneal dialysis as a result of renal impairment. They often require broad-spectrum antibiotics for the treatment of ongoing infections or as prophylactic therapy and have an increased risk of fungal infection. Fluconazole is a new thiazole antifungal agent that has been widely used in adults, but its use in children with acute renal impairment requiring peritoneal dialysis has not been documented. The purpose of this investigation was to study the pharmacokinetics of fluconazole in infants and children who developed various degrees of renal impairment, with or without the need for peritoneal dialysis, after major open heart surgery. Between January 1992 and June 1995, 17 children ranging in age from 2 weeks to 3 years (mean, 6 months) who received fluconazole therapy intravenously (3 mg/kg per day for 2 to 3 weeks) after major open heart surgery were enrolled in a prospective study. They were divided into two groups--those who required peritoneal dialysis (PD group; n = 8) and those who did not (non-PD group; n = 9). Blood, urine, and peritoneal dialysate samples were collected for 4 days to determine the pharmacokinetics of the drug, and data were compared between the two groups. The two groups of children had similar demographic characteristics, and their plasma concentrations of fluconazole showed no statistically significant differences. For children dependent on peritoneal dialysis, fluconazole was excreted almost solely through dialysis. Despite a significantly longer terminal elimination half-life for this group of infants, they tended to have a marginally larger volume of distribution of the drug. This, coupled with the continuous hourly exchange of dialysate, provided a large sink volume to effectively remove flu- conazole from the circulation. Thus the plasma clearance and the accumulation ratio were comparable for the two groups of children. Continuous cycling peritoneal dialysis effectively removed fluconazole from the circulation and was the main mode of excretion of the drug in children dependent on dialysis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9385491&dopt=Abstract fluconazole Diflucan



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The Candida albicans CDR3 gene codes for an opaque-phase ABC transporter.

Balan I, Alarco AM, Raymond M.

Institut de Recherches Cliniques de Montreal, Quebec, Canada.

We report the cloning and functional analysis of a third member of the CDR gene family in Candida albicans, named CDR3. This gene codes for an ABC (ATP-binding cassette) transporter of 1,501 amino acids highly homologous to Cdr1p and Cdr2p (56 and 55% amino acid sequence identity, respectively), two transporters involved in fluconazole resistance in C. albicans. The predicted structure of Cdr3p is typical of the PDR/CDR family, with two similar halves, each comprising an N-terminal hydrophilic domain with consensus sequences for ATP binding and a C-terminal hydrophobic domain with six predicted transmembrane segments. Northern analysis showed that CDR3 expression is regulated in a cell-type-specific manner, with low levels of CDR3 mRNA in CAI4 yeast and hyphal cells, high levels in WO-1 opaque cells, and undetectable levels in WO-1 white cells. Disruption of both alleles of CDR3 in CAI4 resulted in no obvious changes in cell morphology, growth rate, or susceptibility to fluconazole. Overexpression of Cdr3p in C. albicans did not result in increased cellular resistance to fluconazole, cycloheximide, and 4-nitroquinoline-N-oxide, which are known substrates for different transporters of the PDR/CDR family. These results indicate that despite a high degree of sequence conservation with C. albicans Cdr1p and Cdr2p, Cdr3p does not appear to be involved in drug resistance, at least to the compounds tested which include the clinically relevant antifungal agent fluconazole. Rather, the high level of Cdr3p expression in WO-1 opaque cells suggests an opaque-phase-associated biological function which remains to be identified.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9393682&dopt=Abstract fluconazole Diflucan



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Effect of iron on fluconazole activity against Candida albicans in presence of human serum or monocyte-derived macrophages.

Minn Y, Brummer E, Stevens DA.

Department of Medicine, Santa Clara Valley Medical Center, San Jose, CA, USA.

Human serum, transferrin, and apotransferrin are known to profoundly inhibit the growth of Candida albicans by iron deprivation. On the other hand, iron overload (iron saturated transferrin) is a serious risk factor for candidiasis in newborn and in leukemic patients. We tested the efficacy of fluconazole and the previously demonstrated synergy of fluconazole and effector cells against C. albicans under iron overload conditions where efficacy might be diminished. We confirm that exogenous iron completely reversed the inhibitory effect of human serum and report that the efficacy of fluconazole against C. albicans was not significantly compromised in a 24 h assay system. Although exogenous iron inhibited fungistatic activity of monocyte-derived macrophages, it did not interfere with the synergistic candidacidal activity of fluconazole and monocyte-derived macrophages. In 72 h assays, where fluconazole had candidacidal activity, exogenous iron did not compromise efficacy of fluconazole, and fluconazole activity was often increased. These in vitro results suggest that effectiveness of fluconazole therapy would not be compromised in iron overload situations in vivo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9404022&dopt=Abstract fluconazole Diflucan