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In vitro comparative efficacy of voriconazole and itraconazole against fluconazole-susceptible and -resistant Cryptococcus neoformans isolates.

Nguyen MH, Yu CY.

Department of Medicine, University of Florida College of Medicine, and VA Medical Center, Gainesville 32610, USA. nguyemt medicine.ufl.edu

In vitro susceptibility testing for 50 clinical isolates of fluconazole-susceptible or -resistant Cryptococcus neoformans was performed with itraconazole and voriconazole. Voriconazole was more potent than itraconazole for fluconazole-susceptible isolates and as potent as itraconazole for fluconazole-susceptible dose-dependent isolates and for fluconazole-resistant isolates. For fluconazole-resistant isolates, the voriconazole and itraconazole MICs ranged from 1 to 2 microg/ml.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9527812&dopt=Abstract fluconazole Diflucan



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The effect of the new triazole, voriconazole (UK-109,496), on the interactions of Candida albicans and Candida krusei with endothelial cells.

Fratti RA, Belanger PH, Sanati H, Ghannoum MA.

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

In this study, we investigated how voriconazole affects specific endothelial cell interactions utilizing both fluconazole-susceptibles and resistantR Candida albicans strains (C. albicansS and C. albicansR, respectively) as well as Candida krusei. Our data show that exposing C. albicansS to voriconazole significantly reduced its adherence to endothelial cells (p <0.001). The adherence of C. albicansR to endothelial cells was not affected by treatment with either antifungal agent. Exposure of C. albicans to both agents inhibited germ tube formation; however, voriconazole showed higher ability in inhibiting germination as compared with fluconazole. The effect of antifungals on germination was also tested during co-incubation of yeast cells with endothelial cells. Pretreated C. albicansS cells germinated on endothelial cells in the presence of voriconazole or fluconazole. However, the degree of germination was reduced by 81% and 16%, respectively. Similar results were observed with C. albicansR. Our data demonstrate that voriconazole treatment reduced the median germ tube length of C. albicansS and C. albicansR by approximately 60%, whereas fluconazole reduced the germ tube length of these strains by 27% and 63%, respectively (P < 0.0001 for each comparison). We compared the efficacy of voriconazole and fluconazole in protecting endothelial cells against damage caused by C. albicansS, C. albicansR, and C. krusei. Voriconazole and fluconazole reduced C. albicans-mediated endothelial cell injury by about 90% and 40%, respectively (P < 0.01 for each comparison). Additionally, voriconazole treatment significantly reduced C. krusei-mediated injury to endothelial cells by 69% (P < 0.01), whereas fluconazole did not exhibit significant protection (P < 0.6). These results demonstrate that voriconazole, in addition to its direct inhibitory activity against fungi, may act against Candida spp. by interfering with critical host/parasite interactions, such as adherence and endothelial cell damage, as well as germination. Therefore, this triazole represents a new and promising agent for the treatment of disseminated candidal infections caused by both fluconazole-susceptible and -resistant species.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9531069&dopt=Abstract fluconazole Diflucan



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Comparative evaluation of FUNGITEST and broth microdilution methods for antifungal drug susceptibility testing of Candida species and Cryptococcus neoformans.

Davey KG, Holmes AD, Johnson EM, Szekely A, Warnock DW.

Mycology Reference Laboratory, Public Health Laboratory Service, Bristol, United Kingdom.

The FUNGITEST method (Sanofi Diagnostics Pasteur, Paris, France) is a microplate-based procedure for the breakpoint testing of six antifungal agents (amphotericin B, flucytosine, fluconazole, itraconazole, ketoconazole, and miconazole). We compared the FUNGITEST method with a broth microdilution test, performed according to National Committee for Clinical Laboratory Standards document M27-A guidelines, for determining the in vitro susceptibilities of 180 isolates of Candida spp. (50 C. albicans, 50 C. glabrata, 10 C. kefyr, 20 C. krusei, 10 C. lusitaniae, 20 C. parapsilosis, and 20 C. tropicalis isolates) and 20 isolates of Cryptococcus neoformans. Overall, there was 100% agreement between the methods for amphotericin B, 95% agreement for flucytosine, 84% agreement for miconazole, 83% agreement for itraconazole, 77% agreement for ketoconazole, and 76% agreement for fluconazole. The overall agreement between the methods exceeded 80% for all species tested with the exception of C. glabrata (71% agreement). The poorest agreement between the results for individual agents was seen with C. glabrata (38% for fluconazole, 44% for ketoconazole, and 56% for itraconazole) and C. tropicalis (50% for miconazole). The FUNGITEST method misclassified as susceptible 2 of 12 (16.6%) fluconazole-resistant isolates, 2 of 10 (20%) itraconazole-resistant isolates, and 4 of 8 (50%) ketoconazole-resistant isolates of several Candida spp. Further development of the FUNGITEST procedure will be required before it can be recommended as an alternative method for the susceptibility testing of Candida spp. or C. neoformans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9542910&dopt=Abstract fluconazole Diflucan



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Accumulation of fluconazole in scalp hair.

Yeates R, Laufen H, Zimmermann T, Scharpf F.

Department of Pharmacology, Pfizer Mack Development Centre, Illertissen, Germany.

The accumulation in scalp hair of the antimycotic triazole, fluconazole, was studied during and after administration. Fluconazole 50 mg was administered to 12 healthy subjects as a single capsule each day for 28 days. The concentration of fluconazole 5 hours after administration was measured in different 1-cm sections of scalp hair at intervals during treatment and for 6 months after the end of treatment. In each section of scalp hair the concentration of fluconazole increased during treatment and was consistently higher than values found in plasma. For example, the mean concentration in the first hair section on day 28, 19.8 micrograms/g, corresponded to a mean penetration ratio relative to plasma of 9.42. During administration, the maximal concentration of fluconazole was found in the first hair section. After cessation of administration, the measured concentrations of fluconazole decreased and greater concentrations were found in the distal hair sections, presumably as a result of hair growth. Fluconazole was detectable, however, in the hair of 9 of the 12 subjects even 6 months after treatment. The mean concentration of fluconazole in hair bulbs on day 28 was 12.1 micrograms/g (n = 6), corresponding to a mean penetration ratio of 5.99. In a second study, fluconazole was administered as a single oral 150-mg capsule per week for 4 weeks to a group of 8 healthy subjects. The mean fluconazole concentration in whole scalp hair 5 hours after the last dose was 3.2 micrograms/g.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9549644&dopt=Abstract fluconazole Diflucan



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Thirteen-year evolution of azole resistance in yeast isolates and prevalence of resistant strains carried by cancer patients at a large medical center.

Boschman CR, Bodnar UR, Tornatore MA, Obias AA, Noskin GA, Englund K, Postelnick MA, Suriano T, Peterson LR.

Department of Pathology, Northwestern Memorial Hospital and Northwestern University Medical School, Chicago, Illinois 60611, USA.

Drug resistance is emerging in many important microbial pathogens, including Candida albicans. We performed fungal susceptibility tests with archived isolates obtained from 1984 through 1993 and fresh clinical isolates obtained from 1994 through 1997 by testing their susceptibilities to fluconazole, ketoconazole, and miconazole and compared the results to the rate of fluconazole use. All isolates recovered prior to 1993 were susceptible to fluconazole. Within 3 years of widespread azole use, we detected resistance to all agents in this class. In order to assess the current prevalence of resistant isolates in our hematologic malignancy and transplant patients, we obtained rectal swabs from hospitalized, non-AIDS, immunocompromised patients between June 1995 and January 1996. The swabs were inoculated onto sheep's blood agar plates containing 10 microg of vancomycin and 20 microg of gentamicin/ml of agar. One hundred one yeasts were recovered from 97 patients and were tested for their susceptibilities to amphotericin B, fluconazole, flucytosine, ketoconazole, and miconazole. The susceptibility pattern was then compared to those for all clinical isolates obtained throughout the medical center. The antifungal drug histories for each patient were also assessed. The yeasts from this surveillance study were at least as susceptible as the overall hospital strains. There did not appear to be a direct linkage between prior receipt of antifungal agent therapy and carriage of a new, drug-resistant isolate. Increased resistance to newer antifungal agents has occurred at our medical center, but it is not focal to any high-risk patient population that we studied. Monitoring of susceptibility to antifungal agents appears to be necessary for optimizing clinical therapeutic decision making.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9559774&dopt=Abstract fluconazole Diflucan



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Susceptibilities of clinical and laboratory isolates of Blastomyces dermatitidis to ketoconazole, itraconazole, and fluconazole.

Chapman SW, Rogers PD, Rinaldi MG, Sullivan DC.

Department of Microbiology, School of Medicine, University of Mississippi Medical Center, Jackson 39216-4505, USA. schapman umsmed.edu

Eighteen isolates of Blastomyces dermatitidis were evaluated for their in vitro susceptibilities to ketoconazole, itraconazole, and fluconazole. The MIC ranges were 0.1 to 0.4 microg/ml for ketoconazole, < or =0.018 to 0.07 microg/ml for itraconazole, and 2.5 to 4.0 microg/ml for fluconazole. The ranges for the minimal lethal concentrations were 0.2 to 0.8 microg/ml for ketoconazole, < or =0.018 to 0.07 microg/ml for itraconazole, and 10 to 40 microg/ml for fluconazole. Itraconazole was the most active agent against B. dermatitidis in vitro, while fluconazole was the least active. These results correlate with the clinical efficacies noted to date with doses of these agents used to treat blastomycosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9559827&dopt=Abstract fluconazole Diflucan



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Correlation of in vitro fluconazole susceptibility with clinical outcome for severely ill patients with oropharyngeal candidiasis.

Arikan S, Akova M, Hayran M, Ozdemir O, Erman M, Gur D, Unal S.

Department of Clinical Microbiology, Hacettepe University School of Medicine, Ankara, Turkey.

We investigated the correlation between in vitro susceptibility to fluconazole and clinical response in severely ill patients with oropharyngeal candidiasis treated with fluconazole. The study included 48 adult patients, of whom 23 were neutropenic (absolute neutrophil count, < 500/mm3). Forty-eight isolates (20 Candida albicans, 12 Candida krusei, 10 Candida kefyr, 3 Torulopsis glabrata, and 3 Candida tropicalis) were tested for susceptibility to fluconazole with use of the macrodilution method of the National Committee for Clinical Laboratory Standards. A strain was considered to be susceptible to fluconazole if the MIC was < or = 8 micrograms/mL and resistant if the value was > or = 64 micrograms/mL. All but one of the resistant strains were C. krusei isolates. Species of causative Candida, persistent neutropenia, and susceptibility to fluconazole were significant predictors of clinical response by univariate analysis. Logistic regression analysis indicated that the only significant factor was the species of Candida isolates, validating the recently recommended MIC breakpoint and the correlation between clinical outcome and in vitro antifungal susceptibility.

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Clinical evaluation and microbiology of oropharyngeal infection due to fluconazole-resistant Candida in human immunodeficiency virus-infected patients.

Revankar SG, Dib OP, Kirkpatrick WR, McAtee RK, Fothergill AW, Rinaldi MG, Redding SW, Patterson TF.

University of Texas Health Science Center at San Antonio 78284-7881, USA.

Signs and symptoms of oropharyngeal candidiasis (OPC) were correlated with microbiology and clinical response to fluconazole in a cohort of patients with advanced human immunodeficiency virus (HIV) infection and recurrent OPC. Sixty-four HIV-infected patients with a median CD4 cell count of < 50/mm3 (range, 3-318/mm3) who presented with OPC were enrolled in a longitudinal study. Specimens for cultures were taken weekly until clinical resolution. Therapy with fluconazole was increased weekly as required to a maximum daily dose of 800 mg until resolution of symptoms and oral lesions. Resistant or dose-dependent susceptible yeasts, defined as a minimum inhibitory concentration of > or = 16 micrograms/mL, were detected in 48 (31%) of 155 episodes. Clinical resolution with fluconazole therapy occurred in 107 (100%) of 107 episodes with susceptible yeasts vs. 44 (92%) of 48 episodes with resistant or dose-dependent susceptible strains (P = .008). Patients from whom fluconazole-resistant yeasts were isolated required longer courses of therapy and higher doses of fluconazole for response, but overall, excellent responses to fluconazole were seen in patients with advanced HIV infection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9564483&dopt=Abstract fluconazole Diflucan