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Comparison of three methods for testing azole susceptibilities of Candida albicans strains isolated sequentially from oral cavities of AIDS patients.

Tortorano AM, Viviani MA, Barchiesi F, Arzeni D, Rigoni AL, Cogliati M, Compagnucci P, Scalise G.

Istituto di Igiene e Medicina Preventiva, Universita degli Studi di Milano-IRCCS Ospedale Maggiore di Milano, Milan, Italy.

Three susceptibility testing procedures were compared to determine fluconazole, itraconazole, and ketoconazole MICs against 47 Candida albicans strains isolated sequentially from the oral cavities of five AIDS patients undergoing azole therapy. They included the broth microdilution method (BM), performed according to the National Committee for Clinical Laboratory Standards' tentative standard, the agar dilution method (AD), and the Etest; the latter two tests were performed both in Casitone agar (AD-Cas and Etest-Cas) and in RPMI (AD-RPMI and Etest-RPMI). Twenty-four- and 48-h MICs obtained by AD and Etest were compared with 48-h MICs obtained by BM. The MICs of all the azoles determined by BM were usually lower than those obtained by the other methods, mainly due to different reading criteria. In order to assess the most appropriate way of evaluating the agreement of MICs obtained by different methods with those produced by the proposed reference method (BM), we used the mean differences calculated according to Bland and Altman's method. Comparison of fluconazole MICs obtained by BM and AD-Cas yielded a mean difference of 3, and the percentages of agreement within +/-2 dilutions were 98 and 100% at 24 and 48 h, respectively. For ketoconazole and itraconazole MICs, lower mean differences were noted, and agreement ranged from 96 to 100%. Agreement between the AD-RPMI and BM results was poor for all azoles, and an increase in MICs was always observed between the 1st- and 2nd-day readings. Similarly, Etest-Cas gave better agreement with BM than did Etest-RPMI for all the azoles. BM, AD-Cas, and Etest-Cas each demonstrated a progressive increase in fluconazole MICs against strains isolated sequentially from a given patient, in accordance with the decreased clinical response to fluconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9620380&dopt=Abstract fluconazole Diflucan



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Assessment of antifungal activities of fluconazole and amphotericin B administered alone and in combination against Candida albicans by using a dynamic in vitro mycotic infection model.

Lewis RE, Lund BC, Klepser ME, Ernst EJ, Pfaller MA.

University of Iowa College of Pharmacy, Iowa City 52242-1112, USA.

We evaluated the pharmacodynamic activities of fluconazole and amphotericin B given alone and in combination against Candida albicans by using an in vitro model of bloodstream infection that simulates human serum pharmacokinetic parameters for these antifungals. Fluconazole was administered as a bolus into the model to simulate regimens of 200 mg every 24 h (q24 h) and 400 mg q24 h. Amphotericin B was administered at doses producing the peak concentration (2.4 micrograms/ml) observed with a regimen of 1 mg/kg of body weight q24 h. A combination regimen of fluconazole (400 mg q24 h) and amphotericin B (1 mg/kg q24 h) administered simultaneously and as a staggered regimen (amphotericin B bolus given 8 h after fluconazole bolus) was also simulated in the model to characterize possible antagonism between these agents. Fluconazole alone and amphotericin B alone demonstrated fungistatic (< 99.9% reduction in numbers of CFU per milliliter from the starting inoculum) and fungicidal (> 99.9% reduction) activity, respectively. When fluconazole and amphotericin B were administered simultaneously, fungicidal activity similar to that observed with amphotericin B alone was observed. Staggered administration of fluconazole and amphotericin B, however, resulted in a substantial reduction of the fungicidal activity of amphotericin B, producing fungistatic activity similar to that observed with noncombination fluconazole regimens. These results demonstrate the usefulness of this model for comparing the in vitro pharmacodynamic characteristics of different antifungal regimens and support the theory of azole-polyene antagonism. The effects of this antagonism on the in vivo activity and clinical usefulness of combination antifungal therapy, however, remain to be determined.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9624480&dopt=Abstract fluconazole Diflucan



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Pharmacokinetic studies of fluconazole in rabbits characterizing doses which achieve peak levels in serum and area under the concentration-time curve values which mimic those of high-dose fluconazole in humans.

Louie A, Liu QF, Drusano GL, Liu W, Mayers M, Anaissie E, Miller MH.

Division of Infectious Diseases, Albany Medical College, New York 12208, USA.

We conducted steady-state pharmacokinetic studies with high-dose fluconazole with rabbits and human volunteers. We then derived mathematical equations that predict the doses of fluconazole that should be given to rabbits to produce 24-h area under the concentration-time curve values and maximum concentrations in serum that are similar to those measured for humans given 800 to 2,000 mg of fluconazole per day. These equations provide a rational basis for designing future efficacy studies with rabbits and in evaluating the strength with which results of previously conducted studies using rabbit infection models can be extrapolated to the clinic.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9624506&dopt=Abstract fluconazole Diflucan



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Impact of fluconazole administration on outcomes in critically ill patients.

Garrelts JC, Schroeder TR, Harrison PB.

Clinical Pharmacy Services and Research, Wesley Medical Center, Wichita, KS, USA. Jim.Garrelts wesleymc.com

BACKGROUND: Serious infections caused by Candida spp. are an increasingly important cause of morbidity and mortality in critically ill patients. It is unclear which patients will benefit from therapy and at what point to institute treatment. OBJECTIVE: To evaluate the impact of administration of fluconazole therapy in critically ill trauma patients on mortality, length of hospital stay, incidence of deep-seated fungal infection, and positive fungal cultures from any site. METHODS: We conducted a retrospective, matched case-control study of 116 critically ill surgical trauma patients who did or did not receive fluconazole. Patients were followed until hospital discharge or death. A consecutive sample of 58 patients who received fluconazole was selected. A parallel group of patients was evaluated, from which 58 were matched with fluconazole-treated patients based on age (+/- 5 y), gender, and APACHE II score (+/- 3). RESULTS: The groups of patients were well matched, with the exception of central venous catheter placement and broad-spectrum antibiotic use. We found no difference between groups in hospital mortality (21% vs 26%; p = 0.661) or incidence of deep-seated fungal infection (0% vs 2%; p = NS). However, patients receiving fluconazole had a significantly longer stay in both the intensive care unit (ICU) (18 +/- 13 vs 7 +/- 11 days; p < 0.001) and hospital (25 +/- 15 vs 9 +/- 11 days; p < 0.001). Fluconazole patients were significantly more likely to have Candida cultured from sites associated with colonization (43% vs 2%; p < 0.001), possibly explaining why they received fluconazole. CONCLUSIONS: We were unable to detect a benefit from use of fluconazole in our surgical trauma patient population. Isolation of Candida from the mouth or throat alone, in the absence of correlating clinical signs of infection, should not lead to initiation of fluconazole therapy. Fluconazole use should be reserved for carefully selected patients in the trauma ICU setting.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15340132&dopt=Abstract fluconazole Diflucan



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International surveillance of bloodstream infections due to Candida species: frequency of occurrence and antifungal susceptibilities of isolates collected in 1997 in the United States, Canada, and South America for the SENTRY Program. The SENTRY Participant Group.

Pfaller MA, Jones RN, Doern GV, Sader HS, Hollis RJ, Messer SA.

Department of Pathology, University of Iowa College of Medicine, Iowa City 52242, USA. mpfaller blue.weeg.uiowa.edu

An international program of surveillance of bloodstream infections (BSIs) in the United States, Canada, and South America between January and December 1997 detected 306 episodes of candidemia in 34 medical centers (22 in the United States, 6 in Canada, and 6 in South America). Eighty percent of the BSIs were nosocomial and 50% occurred in patients hospitalized in an intensive care unit. Overall, 53.3% of the BSIs were due to Candida albicans, 15.7% were due to C. parapsilosis, 15.0% were due to C. glabrata, 7.8% were due to C. tropicalis, 2.0% were due to C. krusei, 0.7% were due to C. guilliermondii, and 5.8% were due to Candida spp. However, the distribution of species varied markedly by country. In the United States, 43.8% of BSIs were due to non-C. albicans species. C. glabrata was the most common non-C. albicans species in the United States. The proportion of non-C. albicans BSIs was slightly higher in Canada (47.5%), where C. parapsilosis, not C. glabrata, was the most common non-C. albicans species. C. albicans accounted for 40.5% of all BSIs in South America, followed by C. parapsilosis (38.1%) and C. tropicalis (11.9%). Only one BSI due to C. glabrata was observed in South American hospitals. Among the different species of Candida, resistance to fluconazole (MIC, > or = 64 microg/ml) and itraconazole (MIC, > or = 1.0 microg/ml) was observed with C. glabrata and C. krusei and was observed more rarely among other species. Isolates of C. albicans, C. parapsilosis, C. tropicalis, and C. guilliermondii were all highly susceptible to both fluconazole (99.4 to 100% susceptibility) and itraconazole (95.8 to 100% susceptibility). In contrast, 8.7% of C. glabrata isolates (MIC at which 90% of isolates are inhibited [MIC90], 32 microg/ml) and 100% of C. krusei isolates were resistant to fluconazole, and 36.9% of C. glabrata isolates (MIC90, 2.0 microg/ml) and 66.6% of C. krusei isolates were resistant to itraconazole. Within each species there were no geographic differences in susceptibility to fluconazole or itraconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9650930&dopt=Abstract fluconazole Diflucan



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Glucuronidation of 3'-azido-3'-deoxythymidine (zidovudine) by human liver microsomes: relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and valproic acid.

Trapnell CB, Klecker RW, Jamis-Dow C, Collins JM.

Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20852, USA. trapnelc globomax.com

Zidovudine (3'-azido-3'-deoxythymidine [AZT]), an antiviral nucleoside analog effective in the treatment of human immunodeficiency virus infection, is primarily metabolized to an inactive glucuronide form, GAZT, via uridine-5'-diphospho-glucuronosyltransferase (UGT) enzymes. UGT enzymes exist as different isoforms, each exhibiting substrate specificity. Published clinical studies have shown that atovaquone, fluconazole, methadone, and valproic acid decreased GAZT formation, presumably due to UGT inhibition. The effect of these drugs on AZT glucuronidation was assessed in vitro by using human hepatic microsomes to begin understanding in vitro-in vivo correlations for UGT metabolism. The concentrations of each drug studied were equal to those reported with the usual clinical doses and at concentrations at least 10 times higher than would be expected with these doses. High-performance liquid chromatography was used to assess the respective metabolism and formation of AZT and GAZT. All four drugs exhibited concentration-dependent inhibition of AZT glucuronidation. The respective concentrations of atovaquone and methadone which caused 50% inhibition of GAZT were > 100 and 8 micrograms/ml, well above their usual clinical concentrations. Fluconazole and valproic acid exhibited 50% inhibition of GAZT at 50 and 100 micrograms/ml, which are within the clinical ranges of 10 to 100 and 50 to 100 micrograms/ml, respectively. These data suggest that inhibition of AZT glucuronidation may be more clinically significant with concomitant fluconazole and valproic acid. Factors such as inter- and intraindividual pharmacokinetic variability and changes in AZT intracellular concentrations should be considered as other mechanisms responsible for changes in AZT pharmacokinetics with concomitant therapies.

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Fluconazole resistance associated with drug efflux and increased transcription of a drug transporter gene, PDH1, in Candida glabrata.

Miyazaki H, Miyazaki Y, Geber A, Parkinson T, Hitchcock C, Falconer DJ, Ward DJ, Marsden K, Bennett JE.

Clinical Mycology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Sequential Candida glabrata isolates were obtained from the mouth of a patient infected with human immunodeficiency virus type 1 who was receiving high doses of fluconazole for oropharyngeal thrush. Fluconazole-susceptible colonies were replaced by resistant colonies that exhibited both increased fluconazole efflux and increased transcripts of a gene which codes for a protein with 72.5% identity to Pdr5p, an ABC multidrug transporter in Saccharomyces cerevisiae. The deduced protein had a molecular mass of 175 kDa and was composed of two homologous halves, each with six putative transmembrane domains and highly conserved sequences of ATP-binding domains. When the earliest and most azole-susceptible isolate of C. glabrata from this patient was exposed to fluconazole, increased transcripts of the PDR5 homolog appeared, linking azole exposure to regulation of this gene.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9661006&dopt=Abstract fluconazole Diflucan



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Identification and expression of multidrug transporters responsible for fluconazole resistance in Candida dubliniensis.

Moran GP, Sanglard D, Donnelly SM, Shanley DB, Sullivan DJ, Coleman DC.

Department of Oral Surgery, Oral Medicine and Pathology, School of Dental Science, Trinity College, University of Dublin, Republic of Ireland.

Candida dubliniensis is a recently described Candida species associated with oral candidosis in human immunodeficiency virus (HIV)-infected and AIDS patients, from whom fluconazole-resistant clinical isolates have been previously recovered. Furthermore, derivatives exhibiting a stable fluconazole-resistant phenotype have been readily generated in vitro from fluconazole-susceptible isolates following exposure to the drug. In this study, fluconazole-resistant isolates accumulated up to 80% less [3H] fluconazole than susceptible isolates and also exhibited reduced susceptibility to the metabolic inhibitors 4-nitroquinoline-N-oxide and methotrexate. These findings suggested that C. dubliniensis may encode multidrug transporters similar to those encoded by the C. albicans MDR1, CDR1, and CDR2 genes (CaMDR1, CaCDR1, and CaCDR2, respectively). A C. dubliniensis homolog of CaMDR1, termed CdMDR1, was cloned; its nucleotide sequence was found to be 92% identical to the corresponding CaMDR1 sequence, while the predicted CdMDR1 protein was found to be 96% identical to the corresponding CaMDR1 protein. By PCR, C. dubliniensis was also found to encode homologs of CDR1 and CDR2, termed CdCDR1 and CdCDR2, respectively. Expression of CdMDR1 in a fluconazole-susceptible delta pdr5 null mutant of Saccharomyces cerevisiae conferred a fluconazole-resistant phenotype and resulted in a 75% decrease in accumulation of [3H]fluconazole. Northern analysis of fluconazole-susceptible and -resistant isolates of C. dubliniensis revealed that fluconazole resistance was associated with increased expression of CdMDR1 mRNA. In contrast, most studies showed that overexpression of CaCDR1 was associated with fluconazole resistance in C. albicans. Increased levels of the CdMdr1p protein were also detected in fluconazole-resistant isolates. Similar results were obtained with fluconazole-resistant derivatives of C. dubliniensis generated in vitro, some of which also exhibited increased levels of CdCDR1 mRNA and CdCdr1p protein. These results demonstrate that C. dubliniensis encodes multidrug transporters which mediate fluconazole resistance in clinical isolates and which can be rapidly mobilized, at least in vitro, on exposure to fluconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9661028&dopt=Abstract fluconazole Diflucan