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L-proline as a nitrogen source increases the susceptibility of Saccharomyces cerevisiae S288c to fluconazole.

Stella CA, Costanzo R, Burgos HI, Saenz DA, Venerus RD.

Biochemistry Department, School of Medicine, Buenos Aires University, Argentina.

Fluconazole inhibition of Saccharomyces cerevisiae S288c growth was evaluated in media containing ammonia, L-proline or L-leucine as a nitrogen source. Growth inhibition by fluconazole was maximum when L-proline was used as a nitrogen source, while rhodamine 6G accumulation and fluconazole resistance were the highest when ammonia was the sole nitrogen source.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9821294&dopt=Abstract fluconazole Diflucan



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The effect of limited exposure to antimycotics on the relative cell-surface hydrophobicity and the adhesion of oral Candida albicans to buccal epithelial cells.

Ellepola AN, Samaranayake LP.

Faculty of Dentistry, Prince Philip Dental Hospital, University of Hong Kong.

Candida albicans is the major aetiological agent of oral candidosis. Adhesion to oral mucosal surfaces is considered a prerequisite for its successful colonization and subsequent infection, and its relative cell-surface hydrophobicity (CSH) is a contributory physical force. Thus, the main aim here was to determine the CSH of 10 isolates of oral C. albicans after a short exposure to sublethal concentrations of four antifungal agents and to correlate these findings with their adhesion to human buccal epithelial cells (BEC). The yeasts were exposed to sublethal concentrations of nystatin [x 6 minimal inhibitory concentration (MIC)], 5-fluorocytosine (x 8 MIC), ketoconazole (x 4 MIC) and fluconazole (x 4 MIC) for 1 h. The drug was then removed, and the CSH and BEC adhesion assessed by a biphasic aqueous-hydrocarbon assay and a microscopic method, respectively. The mean percentage reductions of CSH after exposure to nystatin, 5-fluorocytosine, ketoconazole and fluconazole were 27.14% (p = 0.01), 9.46% (p = 0.43), 19.47% (p = 0.04) and 6.16% (p = 0.59). Similarly, exposure to all the drugs except 5-fluorocytosine resulted in a significant inhibition of yeast adhesion to BEC, with nystatin eliciting the highest and fluconazole the least inhibition. Further, on regression analysis a strong positive correlation was observed between CSH and adhesion to BEC after limited exposure to 5-fluorocytosine (r = 0.48, p < 0.0001), ketoconazole (r = 0.48, p < 0.0001), fluconazole (r = 0.55, p < 0.0001) as well as in the unexposed controls (r = 0.41, p = 0.001), although nystatin was an exception (r = 0.09, p = 0.44). Taken together, these data elucidate further mechanisms by which antimycotics may operate in vivo to suppress candidal pathogenicity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9821511&dopt=Abstract fluconazole Diflucan



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Increasing in vitro resistance to fluconazole in Cryptococcus neoformans Cambodian isolates: April 2000 to March 2002.

Sar B, Monchy D, Vann M, Keo C, Sarthou JL, Buisson Y.

Laboratory of Medical Microbiology, Unit of Clinical Testing, Institut Pasteur du Cambodge, 5 Boulevard Monivong, BP 983, Phnom Penh, Cambodia. sborann pasteur-kh.org

OBJECTIVES: Cryptococcal meningitis is the third-most-common opportunistic infection in HIV patients in Cambodia. Hospitalized patients were given amphotericin B for initial therapy followed by fluconazole for maintenance therapy. The antifungal drug susceptibility of Cryptococcus neoformans isolated from cerebrospinal fluid (CSF) was determined. METHODS: Isolates of C. neoformans were collected during active laboratory-based surveillance, the first batch from April 2000 to March 2001 (134 new cases), the second batch from April 2001 to March 2002 (268 new cases). Etest strips were used to determine the MICs of amphotericin B and fluconazole. The antigenic agglutination slide test was used for serotyping. RESULTS: The MIC(50)s and MIC(90)s of fluconazole changed significantly from year 2000 to 2002; the MIC(50)s increased from 4 to 12 mg/L, and the MIC(90)s from 12 to 96 mg/L. For amphotericin B, the MIC(50)s and MIC(90)s remained stable. Moreover, in the second batch, fluconazole MICs were >/=256 mg/L for 20 isolates. By serotyping, it was found that 98.5% of the isolates were serotype A. CONCLUSIONS: C. neoformans strains isolated from CSF of AIDS patients in Cambodia remain susceptible in vitro to amphotericin B. These strains are less susceptible in vitro to fluconazole, 2.5% being resistant in the first year and 14% in the second year of study. Nevertheless, in vitro resistance of C. neoformans to fluconazole appeared to be linked to extended maintenance treatments.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15254027&dopt=Abstract fluconazole Diflucan



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Declining rates of oropharyngeal candidiasis and carriage of Candida albicans associated with trends toward reduced rates of carriage of fluconazole-resistant C. albicans in human immunodeficiency virus-infected patients.

Martins MD, Lozano-Chiu M, Rex JH.

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

In order to determine the current prevalence and incidence of fluconazole-resistant oropharyngeal candidiasis among human immunodeficiency virus (HIV)-infected patients, we conducted a prospective observational study of a consecutive series of HIV-infected patients. Of 128 enrolled patients, 70 patients completed four quarterly follow-up visits over a period of 1 year. Over this period, declining rates of carriage of Candida albicans (from 61% to 39%; P = .008) and of oropharyngeal candidiasis (from 30% to 4%; P < .001) were documented. Trends toward reduction in the frequency of fluconazole-resistant isolates (MIC, > or = 64 micrograms/mL) were also seen. During the survey period, the mean (median) number of antiretroviral agents used per patient rose from 0.5 (0) to 1.8 (2) (P < .001). Thus, rather than progression, we observed declining rates of oropharyngeal candidiasis, C. albicans carriage, and fluconazole-resistant C. albicans in a cohort of HIV-infected patients treated with increasingly effective antiretroviral therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9827284&dopt=Abstract fluconazole Diflucan



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Fungal colonisation and fluconazole therapy in acute liver disease.

Fisher NC, Cooper MA, Hastings JG, Mutimer DJ.

Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, Birmingham, UK.

BACKGROUND/AIMS: Fungal infection, particularly with Candida spp., has been identified as an important cause of morbidity and mortality in patients with acute liver failure. Fungal colonisation of superficial mucosal sites usually precedes invasive infection. We investigated colonisation patterns in patients with acute liver disease receiving fluconazole therapy in order to investigate the possibility of emergence of fluconazole-resistant C. albicans or other species. METHODS: During a 6-month study period, we studied all patients referred to our unit with acute liver disease by twice-weekly sampling and mycological analysis of specimens from superficial mucosal and other sites as appropriate. Patients were treated with prophylactic antimicrobials including 100 mg fluconazole daily in accordance with our usual protocol. RESULTS: Twenty-two patients with acute liver disease were studied, eight of whom underwent transplantation. Eighteen patients were colonised by fungi at presentation, and six developed secondary colonisation during fluconazole therapy. Four of these patients (all transplanted) became colonised by resistant species; one of these was Aspergillus fumigatus, which led to death. There were no other invasive fungal infections identified during the study period, and no fluconazole-resistant C. albicans were identified. CONCLUSIONS: Resistance to fluconazole is unlikely to develop in C. albicans during short-term fluconazole prophylaxis in acute liver disease, and in this study we did not find evidence of invasive disease from other Candida spp. during fluconazole therapy. However, in patients at particularly high risk, other strategies are required to prevent infection with Aspergillus spp.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9831360&dopt=Abstract fluconazole Diflucan



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Multiple molecular mechanisms contribute to a stepwise development of fluconazole resistance in clinical Candida albicans strains.

Franz R, Kelly SL, Lamb DC, Kelly DE, Ruhnke M, Morschhauser J.

Zentrum fur Infektionsforschung, Universitat Wurzburg, D-97070 W urzburg, Germany.

From each of two AIDS patients with oropharyngeal candidiasis, five Candida albicans isolates from recurrent episodes of infection which became gradually resistant against fluconazole during antimycotic treatment were analyzed for molecular changes responsible for drug resistance. In both patients, a single C. albicans strain was responsible for the recurrent infections, but the CARE-2 fingerprint pattern of the isolates exhibited minor genetic alterations, indicating that microevolution of the strains took place during fluconazole therapy. In the isolates from patient 1, enhanced mRNA levels of the MDR1 gene, encoding a multiple drug resistance protein from the superfamily of major facilitators, and constitutive high expression of the ERG11 gene, coding for the drug target enzyme sterol 14alpha-demethylase, correlated with a stepwise development of fluconazole resistance. The resistant strains exhibited reduced accumulation of fluconazole and, for the last in the series, a slight increase in drug needed to inhibit sterol 14alpha-demethylation in vitro. In the isolates from patient 2, increased MDR1 mRNA levels and the change from heterozygosity to homozygosity for a mutant form of the ERG11 gene correlated with continuously decreased drug susceptibility. In this series, reduced drug accumulation and increased resistance in the target enzyme activity, sterol 14alpha-demethylase, were observed. These results demonstrate that different molecular mechanisms contribute to a gradual development of fluconazole resistance in C. albicans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9835492&dopt=Abstract fluconazole Diflucan



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In vitro susceptibilities of Candida bloodstream isolates to the new triazole antifungal agents BMS-207147, Sch 56592, and voriconazole.

Pfaller MA, Messer SA, Hollis RJ, Jones RN, Doern GV, Brandt ME, Hajjeh RA.

Department of Pathology, University of Iowa College of Medicine, Iowa City, Iowa, USA. michael-pfaller uiowa.edu

BMS-207147, Sch 56592, and voriconazole are three new investigational triazoles with broad-spectrum antifungal activity. The in vitro activities of these three agents were compared with those of itraconazole and fluconazole against 1,300 bloodstream isolates of Candida species obtained from over 50 different medical centers in the United States. The MICs of all of the antifungal drugs were determined by broth microdilution tests performed according to the National Committee for Clinical Laboratory Standards method using RPMI 1640 as a test medium. BMS-207147, Sch 56592, and voriconazole were all quite active against all Candida sp. isolates (MICs for 90% of the isolates tested [MIC90s], 0.5, 1.0, and 0.5 microgram/ml, respectively). Candida albicans was the most susceptible species (MIC90s, 0.03, 0.06, and 0.06 microgram/ml, respectively), and C. glabrata was the least susceptible (MIC90s, 4. 0, 4.0, and 2.0 microgram/ml, respectively). BMS-207147, Sch 56592, and voriconazole were all more active than itraconazole and fluconazole against C. albicans, C. parapsilosis, C. tropicalis, and C. krusei. There existed a clear rank order of in vitro activity of the five azoles examined in this study when they were tested versus C. glabrata: voriconazole > BMS-207147 = Sch 56592 = itraconazole > fluconazole (MIC90s, 2.0, 4.0, 4.0, 4.0, and 64 microgram/ml, respectively). For isolates of Candida spp. with decreased susceptibility to both itraconazole and fluconazole, the MICs of BMS-207147, Sch 56592, and voriconazole were also elevated. These results suggest that BMS-207147, Sch 56592, and voriconazole all possess promising antifungal activity and that further in vitro and in vivo investigations are warranted to establish the clinical value of this improved potency.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9835520&dopt=Abstract fluconazole Diflucan



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Fluconazole sensitivities of Candida species isolated from the mouths of terminally ill cancer patients.

Ball K, Sweeney MP, Baxter WP, Bagg J.

University of Glasgow Dental School, Scotland.

Oral candidosis is common in advanced cancer and is often treated with the systemic triazole antifungal drug fluconazole. This study examined the species of yeast present in the mouths of 30 patients with advanced cancer and determined their sensitivity to fluconazole. Thirty-five yeast isolates were collected from a total of 25 (83 percent) of the patients sampled. The two most common species were Candida albicans (15 isolates) and C. glabrata (11 isolates)--with smaller numbers of C. tropicalis, C. parapsilosis, C. guilliermondii, C. inconspicua, and Saccharomyces cerevisiae. The minimal inhibitory concentrations (MIC) of fluconazole for the strains of C. albicans were generally low (median 0.19 microgram/ml) but were considerably higher for C. glabrata (median 2 micrograms/ml). The remaining species demonstrated MICs similar to those for C. albicans, with the exceptions of C. inconspicua and Saccharomyces cerevisiae, which were relatively insensitive. In conclusion, non-albicans yeasts are common in the mouths of patients with advanced cancer and these may have reduced sensitivity to fluconazole. Mycological diagnosis is a valuable aid to management.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9866454&dopt=Abstract fluconazole Diflucan