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Fluconazole in the management of neonatal systemic candidiasis.

Narang A, Agrawal P, Chakraborti A, Kumar P.

Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh.

OBJECTIVE: To evaluate the role of Fluconazole in the management of neonatal systemic candidiasis. DESIGN: Descriptive, retrospective analysis. SUBJECTS: 23 neonates diagnosed as systemic candidiasis based on clinical suspicion with blood and/or urine culture positive for candida were treated with Fluconazole (5 mg/kg/day) for > 7 days. RESULTS: Babies had mean birth weight 1590 + 533 g, mean gestation 32.3 + 3.1 wks and fungal sepsis was diagnosed at a mean age of 14.3 + 7.9 days. Candida albicans (43.5%), C. tropicalis (21.7%), C. guillermondii (13%), C. parapsillosis (13%) and C. krusei (8.7%) were the species isolated. Fluconazole was effective in 82.3% cases with no side effects. Four resistant cases were C. parapsillosis (n = 2), C. albicans (n = 1) and C. guillermondii (n = 1) and there were three deaths, all in resistant cases though one death was unrelated to candidemia. CONCLUSION: Fluconazole is a safe and effective drug for neonatal systemic candidiasis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9057379&dopt=Abstract fluconazole Diflucan



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Inhibition and interaction of cytochrome P450 of Candida krusei with azole antifungal drugs.

Venkateswarlu K, Denning DW, Kelly SL.

Krebs's Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, UK.

Candida krusei has become an increasingly important invasive pathogen, particularly in AIDS patients and is highly resistant to fluconazole. In vitro growth inhibition studies revealed that fluconazole and ketoconazole were approximately 800- and 19-fold less inhibitory than itraconazole. The inhibition and interaction of itraconazole, fluconazole and ketoconazole with the sterol 14 alpha-demethylase of C. krusei was studied using in vitro ergosterol biosynthesis and difference spectroscopy, respectively. Both itraconazole and ketoconazole inhibited in vitro ergosterol biosynthesis at lower concentrations than fluconazole. All three drugs interacted with microsomal P450 and interfered in the binding of carbon monoxide to P450 in direct proportion to their inhibitory effect on ergosterol biosynthesis in cell-free extracts. The slightly lower affinity of sterol 14 alpha-demethylase for fluconazole compared with itraconazole and ketoconazole is only partially responsible for poor activity of fluconazole on C. krusei.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9061581&dopt=Abstract fluconazole Diflucan



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Fluconazole tolerance in clinical isolates of Cryptococcus neoformans.

Venkateswarlu K, Taylor M, Manning NJ, Rinaldi MG, Kelly SL.

Department of Molecular Biology and Biotechnology, The University of Sheffield, United Kingdom.

Eleven isolates of Cryptococcus neoformans were investigated to determine the biochemical basis of their tolerance to fluconazole. The MICs of fluconazole for three isolates with low-level resistance were 3- to 6-fold higher than those for sensitive isolates, while the MICs for four isolates with high-level resistance were 100- to 200-fold higher than those for sensitive isolates. The level of ergosterol present in the isolates varied, and those which had relatively low levels of ergosterol were resistant to amphotericin B. Changes in the affinity of the target enzyme (sterol 14alpha-demethylase) and decreases in the cellular content of fluconazole seemed to be responsible for the resistance in isolates with low-level and high-level resistance, respectively.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9087482&dopt=Abstract fluconazole Diflucan



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In vitro susceptibilities of clinical yeast isolates to a new echinocandin derivative, LY303366, and other antifungal agents.

Pfaller MA, Messer SA, Coffman S.

Department of Pathology, University of Iowa College of Medicine, Iowa City 52242, USA.

LY303366 is a new semisynthetic echinocandin derivative with potent, broad-spectrum fungicidal activity. We investigated the in vitro activity of LY303366, amphotericin B, flucytosine (5FC), fluconazole, and itraconazole against 435 clinical yeast isolates (413 Candida and 22 Saccharomyces cerevisiae isolates) obtained from over 30 different medical centers. MICs for all five antifungal agents were determined by the National Committee for Clinical Laboratory Standards method with RPMI 1640 test medium. LY303366 was also tested in antibiotic medium 3 as specified by the manufacturer. Overall, LY303366 was quite active against all of the yeast isolates when tested in RPMI 1640 (MIC at which 90% of the isolates are inhibited [MIC90], 1.0 microg/ml) but appeared to be considerably more potent when tested in antibiotic medium 3 (MIC90, 0.03 microg/ml). When tested in antibiotic medium 3, LY303366 was 16- to >2,000-fold more active than itraconazole, fluconazole, amphotericin B, or 5FC against all species except Candida parapsilosis. When tested in RPMI 1640, LY303366 was comparable to amphotericin B and itraconazole and more active than fluconazole and 5FC. All of the isolates for which fluconazole and itraconazole had elevated MICs (> or = 128 and > or = 2.0 microg/ml, respectively) were inhibited by < or = 0.007 microg of LY303366/ml when tested in antibiotic medium 3 and < or = 0.5 microg/ml when tested in RPMI 1640. Based on these studies, LY303366 has promising antifungal activity and warrants further in vitro and in vivo investigation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9087485&dopt=Abstract fluconazole Diflucan



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Patterns of fluconazole susceptibility in isolates from human immunodeficiency virus-infected patients with oropharyngeal candidiasis due to Candida albicans.

Laguna F, Rodriguez-Tudela JL, Martinez-Suarez JV, Polo R, Valencia E, Diaz-Guerra TM, Dronda F, Pulido F.

Servicio de Enfermedades Infecciosas, Centro de Investigacion Clinica, Madrid, Spain.

We evaluated 119 episodes of oropharyngeal candidiasis due to C. albicans to study the patterns of fluconazole susceptibility of the isolates and the characteristics of the patients and to confirm the correlation between fluconazole susceptibility of isolates and therapeutic outcome. Sixty-one isolates were considered susceptible to fluconazole (MICs, < or = 0.5 microg/mL), 33 were intermediate (MICs, 1.0-8.0 microg/mL), and 25 were resistant (MICs, > or = 16.0 microg/mL). Patients infected with resistant strains had significantly lower CD4+ cell counts and a less recent AIDS diagnosis than patients infected with intermediate or susceptible strains. Previous fluconazole therapy and prophylaxis were significantly more frequent for patients infected with resistant and intermediate strains (P < .001). Decreased susceptibility to ketoconazole and itraconazole was observed in resistant and intermediate strains. Fluconazole treatment was ineffective for patients infected with resistant isolates; however, high doses of ketoconazole or itraconazole were successful for nine (81%) of them. Different patterns of fluconazole susceptibility among C. albicans strains are correlated with patients' characteristics and with therapeutic outcomes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9114134&dopt=Abstract fluconazole Diflucan



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Multiple efflux mechanisms are involved in Candida albicans fluconazole resistance.

Albertson GD, Niimi M, Cannon RD, Jenkinson HF.

Department of Oral Biology and Oral Pathology, University of Otago, Dunedin, New Zealand.

Fluconazole-susceptible Candida albicans strains accumulated [3H]fluconazole at a rate of approximately 2 pmol/min per 10(9) cells. Fluconazole accumulation was not affected by the pretreatment of cells with sodium azide or with 2-deoxyglucose. The rate of fluconazole accumulation became saturated at high fluconazole concentrations and was not affected by the addition of ketoconazole, and there was no fluconazole accumulation in cells incubated at 4 degrees C. A fluconazole-resistant mutant of C. albicans SGY-243 was isolated following growth enrichment in fluconazole-containing medium. Cells of the mutant strain, designated FR2, showed a reduced rate of fluconazole accumulation compared with SGY-243 and were not resistant to other azole antifungal agents. The rates of fluconazole accumulation by C. albicans FR2 and the other azole-resistant strains, B59630, AD, and KB, were increased in the presence of sodium azide, suggesting that fluconazole resistance in these strains may be associated with an energy-dependent drug efflux. Fluconazole-resistant C. albicans strains all contained elevated amounts (2- to 17-fold) of mRNA encoding Cdr1, and an ATP-binding cassette-type transporter. In addition, C. albicans FR2 also contained increased amounts of mRNA encoding Benr, a major facilitator superfamily transporter. These results suggest that fluconazole enters C. albicans cells by facilitated diffusion and that fluconazole resistance may involve energy-dependent drug efflux associated with increased expression of Benr and/or Cdr1.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9124851&dopt=Abstract fluconazole Diflucan



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Evaluation of the E test for fluconazole susceptibility testing of Candida albicans isolates from oropharyngeal candidiasis.

Dannaoui E, Colin S, Pichot J, Piens MA.

Universite Claude Bernard Lyon I, Laboratoire de Parasitologie et Mycologie Medicale, Lyon, France.

The aim of the present study was to evaluate the utility of the E test in determining the antifungal susceptibility of Candida albicans. Reproducibility of the E test was determined for amphotericin B, fluconazole, and itraconazole using three different solid media: RPMI 1640, Casitone, and yeast nitrogen base agar. Minimum inhibitory concentrations (MICs) were comparable (results at +/- 2 dilutions) in 92% of the tests for amphotericin B and in 100% for fluconazole and itraconazole. Determination of MIC endpoints was easiest on Casitone agar. Candida albicans isolates from 23 patients undergoing fluconazole therapy for oropharyngeal candidiasis were tested for fluconazole susceptibility. Good correlation was obtained between the MICs of fluconazole and clinical outcome. Clinical failure was associated with strains for which MICs were > or = 48 micrograms/ml. These results suggest that the E test has potential utility for fluconazole susceptibility testing of clinical yeast isolates.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9131326&dopt=Abstract fluconazole Diflucan



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New evidence that Candida albicans possesses additional ATP-binding cassette MDR-like genes: implications for antifungal azole resistance.

Walsh TJ, Kasai M, Francesconi A, Landsman D, Chanock SJ.

Infectious Diseases Section, National Cancer Institute, Bethesda, MD 20892, USA.

Emergence of resistance of Candida albicans to antifungal triazoles is increasingly recognized as an important cause of refractory mucosal candidiasis in HIV-infected patients. Recently, CDR1, which is thought to be analogous to the human MDR-1 P-glycoprotein, has been cloned in C. albicans. It has been proposed that its expression is partially responsible for fluconazole resistance in C. albicans. This gene is characterized by the presence of an ATP binding cassette (ABC) region and is distinct from the BENr gene which does not encode such a functional domain. As the molecular basis for fluconazole resistance appears to be multifactorial, we considered that there may be other ATP binding cassette-containing MDR genes that may potentially contribute to antifungal azole resistance in C. albicans. We therefore sought to identify potential target sequences that may be derived from candidate genes that share homology with the ATP binding cassette region of the human MDR-1 P-glycoprotein. Degenerate oligonucleotide primers based on the known sequence from the ATP binding cassette region of the human MDR-1 P-glycoprotein were used to amplify PCR products within the range of 100 bp in length from C. albicans isolates (3 fluconazole-susceptible and 3 fluconazole-resistant). Sequence analysis of individually subcloned PCR products, derived from the six isolates revealed 34 sequences in total. The results of our study identified 14 clones (with at least one per isolate) with a high degree of homology to the ATP binding cassette of the human MDR-1 P-glycoprotein. The BLAST search did not disclose homology of these new sequences to the C. albicans CDR1 gene, suggesting that C. albicans may possess more than one MDR-like gene. We conclude that C. albicans may possess one or more additional genes encoding ATP binding cassette MDR-like proteins that are distinct from CDR 1 and which could participate in the development of fluconazole resistance.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9147273&dopt=Abstract fluconazole Diflucan