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Synthesis and in vitro antifungal activity of 2-aryl-5-phenylsulfonyl-1,3,4-thiadiazole derivatives.

Foroumadi A, Daneshtalab M, Shafiee A.

Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.

The synthesis and antifungal activity of a series of 2-nitroaryl-5-phenylsulfonyl-1,3,4-thiadiazoles (5a-e) are described. The in vitro antifungal activity of the compounds was determined against a variety of fungal strains in comparison to miconazole (CAS 22916-47-8) and fluconazole (CAS 86386-73-4). Two derivatives (5d, 5e) showed high activity against Candida albicans and Candida spp. having MIC values ranging from 0.048-3.12 micrograms/ml, providing higher potencies than the reference drug fluconazole. Compound 5a also showed high activity against Cryptococcus neoformans (MIC < 0.048 microgram/ml). The activity of this compound against Aspergillus niger and Aspergillus fumigatus was moderate (MIC = 1.56-6.25 micrograms/ml), while fluconazole was inactive. Moreover, the nitroimidazole derivative 5d possessed good activity against most fungal strains in comparison to fluconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10635451&dopt=Abstract fluconazole Diflucan



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Influence of fluconazole at subinhibitory concentrations on cell surface hydrophobicity and phagocytosis of Candida albicans.

Hazen KC, Mandell G, Coleman E, Wu G.

Department of Pathology, P.O. Box 214, University of Virginia Health System, Charlottesville, VA 22908, USA.

Cell surface hydrophobicity (CSH) status influences virulence of Candida albicans and decreases the susceptibility of yeast cells to phagocytic killing. We tested whether subinhibitory concentrations of fluconazole, which is widely used in the treatment and prophylaxis of candidiasis, affect CSH and the susceptibility of C. albicans to enzymatic digestion by glucanase and to phagocytic killing. Treatment of yeast cells with subinhibitory fluconazole concentrations resulted in greater phagocytosis. This effect was independent of CSH but may be related to increased cell wall porosity resulting from alterations in the cell envelope. The use of subinhibitory concentrations of fluconazole in patients with competent phagocytes may contribute to resistance to candidiasis regardless of yeast CSH status.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10650207&dopt=Abstract fluconazole Diflucan



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Preliminary evaluation of a semisolid agar antifungal susceptibility test for yeasts and molds.

Provine H, Hadley S.

Division of Infectious Diseases, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

This report presents a semisolid agar antifungal susceptibility (SAAS) method for the rapid susceptibility screening of yeasts and molds. The reproducibility and accuracy of the SAAS method were assessed by comparing the MICs of amphotericin B and fluconazole obtained for 10 candidate quality control (QC) American Type Culture Collection yeast strains in >/=15 replicates with those found by six independent laboratories using the National Committee for Clinical Laboratory Standards (NCCLS) M27-P broth macrodilution method (M. A. Pfaller et al., J. Clin. Microbiol. 33:1104-1107, 1995). Overall, 96% of MICs for both drugs fell within 1 log(2) dilution of the modal MIC for each strain. The MICs for amphotericin B showed 99% agreement with the NCCLS proposed QC ranges within 1 log(2) dilution. Likewise, the MICs for fluconazole at >/=75% growth reduction showed 99% agreement for seven strains. Three strains, Candida albicans ATCC 24333 and ATCC 76615 and Candida tropicalis ATCC 750, showed a less sharp fluconazole endpoint at >/=75% growth reduction, but at >50% growth reduction, the agreement was 98% within 1 log(2) dilution of the proposed range. The MIC agreement within the proposed range for the suggested QC strains Candida parapsilosis ATCC 22019 and Candida krusei ATCC 6258 was 100% for fluconazole and 100% within 1 log(2) dilution of the proposed range for amphotericin B. The SAAS method demonstrated the susceptibility or resistance of 25 clinical isolates of filamentous fungi such as Aspergillus fumigatus to amphotericin B, itraconazole, and fluconazole, usually within 48 h. Although the results are preliminary, this SAAS method is promising as a rapid and cost-effective screen and is worthy of concerted investigation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10655341&dopt=Abstract fluconazole Diflucan



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Effects of fluconazole administration in critically ill patients: analysis of bacterial and fungal resistance.

Rocco TR, Reinert SE, Simms HH.

Department of Surgery, Brown University, Rhode Island Hospital, Providence 02903, USA.

HYPOTHESIS: The administration of fluconazole in intensive care unit (ICU) patients leads to the emergence of bacterial and fungal resistance. DESIGN: Retrospective analysis of 2 patient cohorts: (1) critically ill patients treated in surgical, trauma, and medical ICUs between June 1997 and January 1999 who did and did not receive fluconazole; and (2) ICU patients with fungal infections and sensitivity testing results from June 1994 to December 1998. SETTING: University-affiliated tertiary care hospital. PATIENTS: The first cohort included 99 ICU patients with documented microorganism culture(s) who were treated with (n = 50) or without (n = 49) fluconazole; the second cohort included 38 patients with Candida species infection, identification, and antifungal susceptibility testing. RESULTS: Mortality (40% vs 20%; P = .03) and hospital length of stay (33.8 vs 25.6 days; P = .04) were higher in the patients treated with fluconazole compared with patients not treated with fluconazole. The ICU length of stay was also higher in patients treated with fluconazole (23.7 vs 15.1 days; P = .009). An increase in bacterial resistance occurred in patients after fluconazole treatment as opposed to bacterial resistance of patients who were treated for bacterial microorganism(s) without fluconazole (16% vs 4%; P = .049). Comparison of patient populations with Candida species identification before and after December 1997 showed an increase in Candida species resistance to fluconazole (11% vs 36%; P = .16), respectively. Fungal strains were dominated by a combination of Candida albicans and Candida glabrata in both populations (60% [before 1998] vs 82% [after 1998]), with an emergence of Candida non-albicans species tolerant to fluconazole. The amount of fluconazole administered and the number of patients receiving fluconazole treatment in the ICUs has also increased when comparing both periods. CONCLUSIONS: Comparison of critically ill patient populations with and without fluconazole treatment found increased mortality and longer hospital and ICU lengths of stay in the fluconazole-treated group. This group also had higher bacterial pathogen resistance to antibiotics after fluconazole administration compared with bacterial resistance of patients without fluconazole treatment. Our results warrant concern regarding worsening bacterial infections, increased mortality, and an increase in Candida resistance to fluconazole from increased use in ICU patients, with a shift in yeast infection that is more difficult to treat.

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Host immune reactivity determines the efficacy of combination immunotherapy and antifungal chemotherapy in candidiasis.

Mencacci A, Cenci E, Bacci A, Bistoni F, Romani L.

Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, 06122 Perugia, Italy.

In immunocompetent mice with candidiasis, successful therapy with amphotericin B and fluconazole relies on the induction of protective, T helper (Th) type 1 responses, an effect potentiated by concomitant interleukin (IL)-4 neutralization. To assess the therapeutic efficacy of combined treatments with antifungals and immunomodulators in conditions of immunosuppression, leukopenic or neutropenic mice with disseminated candidiasis were treated with amphotericin B or fluconazole alone or in combination with soluble IL-4 receptor (sIL-4R) or recombinant (r) IL-12 or IL-10 neutralizing monoclonal antibodies. We found that (1) the synergistic effect of sIL-4R and antifungals is retained in immunocompromised mice; (2) synergism with amphotericin B was superior to that with fluconazole, particularly in leukopenic mice; (3) rIL-12 synergized with fluconazole in neutropenic mice; and (4) IL-10 neutralization was always of limited efficacy. This study indicates that the therapeutic efficacy of antifungals is differentially potentiated by cytokines or cytokine antagonists and is influenced by host immune reactivity.

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In vitro susceptibility of yeasts for fluconazole and itraconazole. Evaluation of a microdilution test.

Nenoff P, Oswald U, Haustein UF.

Department of Dermatology, University of Leipzig, Germany.

In vitro susceptibilities were determined for a total of 159 clinical isolates and 12 reference strains of yeasts belonging to different Candida species including 94 Candida albicans strains, and further genera such as Cryptococcus, Trichosporon, Geotrichum and Saccharomyces. Minimum inhibitory concentration (MIC) values for fluconazole and itraconazole were assessed using a microdilution technique with the semisynthetic high resolution (HR) medium supplemented with glucose and asparagine but without sodium hydrogen carbonate (pH 7.0), according to a proposal of the working group 'Clinical Mycology' of the German Speaking Mycological Society. Fluconazole MIC values for C. albicans were between 0.125 and > or = 128 micrograms ml-1. Thus, the median of 1 microgram ml-1 showed that the overall fluconazole susceptibility was good. As expected, Candida krusei (seven strains) exhibited diminished in vitro susceptibility with MIC values for fluconazole of 8 to 128 micrograms ml-1 with a median of 64 micrograms ml-1. Some Candida kefyr strains seemed to be less susceptible against fluconazole which was indicated by a MIC90 of 64 micrograms ml-1. Surprisingly, no Candida glabrata isolate exhibited a MIC value greater than 16 micrograms ml-1. Other Candida species, Trichosporon cutaneum, Geotrichum candidum and Saccharomyces cerevisiae showed low MICs to fluconazole. In vitro susceptibility testing of itraconazole revealed that all Candida species except C. albicans, but also Trichosporon cutaneum, Geotrichum candidum, and Saccharomyces cerevisiae exhibited acceptable low MIC values against itraconazole (0.03-2 micrograms ml-1). Their MIC90 values for itraconazole were in the close range between 0.125 and 2 micrograms ml-1. MIC values between 0.125 and 2 micrograms ml-1 were obtained, even for C. krusei strains. On the other hand, the range of C. albicans MICs was between 0.0125 and > or = 16 micrograms ml-1 with MIC50 and MIC90 values of 0.125 and > or = 16 micrograms ml-1, respectively, indicating that a considerable number of yeast strains have high MICs. The comparative evaluation of different experimental conditions revealed that there exists a marked influence both of inoculum size and incubation time on the results of susceptibility testing. Therefore, for routine usage 10(2) CFU ml-1 and 18-24 h incubation time for this microdilution method with HR medium are recommended.

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Prophylactic fluconazole promotes reepithelialization in full-face carbon dioxide laser skin resurfacing.

Conn H, Nanda VS.

Beckman Laser Institute and Medical Clinic, Irvine, California 92612, USA. hconn laser.bli.uci.edu

BACKGROUND AND OBJECTIVE: Laser skin resurfacing is used to treat photodamaged skin, rhytids, and acne scarring. Many patients are placed on antibiotics and antivirals pre- and postoperatively. The purpose of this study was to determine whether prophylactic fluconazole increased the rate of reepithelialization in patients undergoing full-face CO(2) laser skin resurfacing. STUDY DESIGN/MATERIALS AND METHODS: Ninety-one patients underwent full-face CO(2) laser skin resurfacing with the Coherent Ultrapulse 5000C. At least two passes of 300 mJ, density 5, were used except periocularly. Study group I consisted of 48 consecutive patients who received either cephalexin or ciprofloxacin for 7 days postoperatively. Study group II consisted of 43 patients who received 300 mg of fluconazole on postoperative days 3-8, in addition to ciprofloxacin. Both groups received acyclovir 400 mg t.i.d. pre- and postoperatively. RESULTS: Time to complete reepithelialization was compared between the groups by t-test. Group II reepithelialized significantly faster than group I (7.65 +/- 1.20 days vs. 10.27 +/- 2.94 days; P < 0.0001). Ninety-five percent of patients receiving fluconazole (group II) healed completely by day 9 versus only 53% of patients in group I. CONCLUSION: Fluconazole administered postoperatively between days 3 and 8 significantly promotes reepithelialization in patients undergoing full-face CO(2) laser skin resurfacing. Copyright 2000 Wiley-Liss, Inc.

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Antifungal penetration into normal rabbit nucleus pulposus.

Conaughty JM, Khurana S, Banovac K, Martinez OV, Eismont FJ.

Department of Orthopedics and Rehabilitation, University of Miami School of Medicine, Miami, Florida 33101, USA. jconaugh hotmail.com

STUDY DESIGN: A rabbit model was used to assess the penetration into the nucleus pulposus of 3 commonly used antifungal medications: amphotericin B, amphotericin B lipid complex, and fluconazole. OBJECTIVES: The purpose of this study was to quantitate the penetration of antifungal medications into the normal rabbit nucleus pulposus. SUMMARY OF BACKGROUND DATA: Fungal infections of the spine are rarely, if ever, treated with medical management alone. Although antibiotic penetration into the nucleus pulposus has been studied extensively, no previous studies have attempted to quantitate the penetration of antifungals into the nucleus pulposus. METHODS: Twenty-four rabbits were given 2 doses of 1 of the antifungal medications studied. One hour after completion of the second dose, the animal was killed and the thoracolumbar spine was excised en bloc. Specimens of nucleus pulposus and serum were obtained and sent to an outside laboratory for analysis. Gas chromatography was used to determine the fluconazole tissue levels, and a bioassay was used to measure amphotericin B tissue levels. RESULTS: Three animals in the amphotericin B group died either after the first or second dose of medication was administered. Although amphotericin B and amphotericin B lipid complex did not show adequate penetration into the nucleus pulposus in 12 out of 12 animals, fluconazole reached therapeutic tissue levels in 5 out of 7 animals. CONCLUSIONS: Fluconazole showed superior penetration into the nucleus pulposus in an uninfected rabbit model when compared to amphotericin B and amphotericin B lipid complex. These findings were found to be statistically significant (P = 0.021), and they suggest that fluconazole may be a better choice for empiric therapy of fungal spine infections while cultures and sensitivities are pending.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15247589&dopt=Abstract fluconazole Diflucan